Method of diagnosing neoplasms

ABSTRACT

The present invention relates generally to nucleic acid molecules, the RNA and protein expression profiles of which are indicative of the onset, predisposition to the onset and/or progression of a neoplasm. More particularly, the present invention is directed to nucleic acid molecules, the expression profiles of which are indicative of the onset and/or progression of a large intestine neoplasm, such as an adenoma or an adenocarcinoma. The expression profiles of the present invention are useful in a range of applications including, but not limited to, those relating to the diagnosis and/or monitoring of colorectal neoplasms, such as colorectal adenocarcinomas. Accordingly, in a related aspect the present invention is directed to a method of screening a subject for the onset, predisposition to the onset and/or progression of a neoplasm by screening for modulation in the expression profile of one or more nucleic acid molecule markers.

FIELD OF THE INVENTION

The present invention relates generally to nucleic acid molecules, the RNA and protein expression profiles of which are indicative of the onset, predisposition to the onset and/or progression of a neoplasm. More particularly, the present invention is directed to nucleic acid molecules, the expression profiles of which are indicative of the onset and/or progression of a large intestine neoplasm, such as an adenoma or an adenocarcinoma. The expression profiles of the present invention are useful in a range of applications including, but not limited to, those relating to the diagnosis and/or monitoring of colorectal neoplasms, such as colorectal adenocarcinomas. Accordingly, in a related aspect the present invention is directed to a method of screening a subject for the onset, predisposition to the onset and/or progression of a neoplasm by screening for modulation in the expression profile of one or more nucleic acid molecule markers.

INCORPORATION BY REFERENCE OF SEQUENCE LISTING

The Sequence Listing in the ASCII text file, named as 26139AB SeqListing.txt of 146 KB, created on Dec. 16, 2016 and submitted to the United States Patent and Trademark Office via EFS-Web, is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Bibliographic details of the publications referred to by author in this specification are collected alphabetically at the end of the description.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Adenomas are benign tumours, or neoplasms, of epithelial origin which are derived from glandular tissue or exhibit clearly defined glandular structures. Some adenomas show recognisable tissue elements, such as fibrous tissue (fibroadenomas) and epithelial structure, while others, such as bronchial adenomas, produce active compounds that might give rise to clinical syndromes.

Adenomas may progress to become an invasive neoplasm and are then termed adenocarcinomas. Accordingly, adenocarcinomas are defined as malignant epithelial tumours arising from glandular structures, which are constituent parts of many organs of the body. The term adenocarcinoma is also applied to tumours showing a glandular growth pattern. These tumours may be sub-classified according to the substances that they produce, for example mucus secreting and serous adenocarcinomas, or to the microscopic arrangement of their cells into patterns, for example papillary and follicular adenocarcinomas. These carcinomas may be solid or cystic (cystadenocarcinomas). Each organ may produce tumours showing a variety of histological types, for example the ovary may produce both mucinous and cystadenocarcinoma.

Adenomas in different organs behave differently. In general, the overall chance of carcinoma being present within an adenoma (i.e. a focus of cancer having developed within a benign lesion) is approximately 5%. However, this is related to size of an adenoma. For instance, in the large bowel (colon and rectum specifically) occurrence of a cancer within an adenoma is rare in adenomas of less than 1 centimetre. Such a development is estimated at 40 to 50% in adenomas which are greater than 4 centimetres and show certain histopathological change such as villous change, or high grade dysplasia. Adenomas with higher degrees of dysplasia have a higher incidence of carcinoma. In any given colorectal adenoma, the predictors of the presence of cancer now or the future occurrence of cancer in the organ include size (especially greater than 9 mm) degree of change from tubular to villous morphology, presence of high grade dysplasia and the morphological change described as “serrated adenoma”. In any given individual, the additional features of increasing age, familial occurrence of colorectal adenoma or cancer, male gender or multiplicity of adenomas, predict a future increased risk for cancer in the organ—so-called risk factors for cancer. Except for the presence of adenomas and its size, none of these is objectively defined and all those other than number and size are subject to observer error and to confusion as to precise definition of the feature in question. Because such factors can be difficult to assess and define, their value as predictors of current or future risk for cancer is imprecise.

Once a sporadic adenoma has developed, the chance of a new adenoma occurring is approximately 30% within 26 months.

Colorectal adenomas represent a class of adenomas which are exhibiting an increasing incidence, particularly in more affluent countries. The causes of adenoma, and of progression to adenocarcinoma, are still the subject of intensive research. To date it has been speculated that in addition to genetic predisposition, environmental factors (such as diet) play a role in the development of this condition. Most studies indicate that the relevant environmental factors relate to high dietary fat, low fibre, low vegetable intake, smoking, obesity, physical inactivity and high refined carbohydrates.

Colonic adenomas are localised areas of dysplastic epithelium which initially involve just one or several crypts and may not protrude from the surface, but with increased growth in size, usually resulting from an imbalance in proliferation and/or apoptosis, they may protrude. Adenomas can be classified in several ways. One is by their gross appearance and the major descriptors include degrees of protrusion: flat sessile (i.e. protruding but without a distinct stalk) or pedunculated (i.e. having a stalk). Other gross descriptors include actual size in the largest dimension and actual number in the colon/rectum. While small adenomas (less than say 5 or 10 millimetres) exhibit a smooth tan surface, pedunculated and especially larger adenomas tend to have a cobblestone or lobulated red-brown surface. Larger sessile adenomas may exhibit a more delicate villous surface. Another set of descriptors include the histopathological classification; the prime descriptors of clinical value include degree of dysplasia (low or high), whether or not a focus of invasive cancer is present, degree of change from tubular gland formation to villous gland formation (hence classification is tubular, villous or tubulovillous), presence of admixed hyperplastic change and of so-called “serrated” adenomas and its subgroups. Adenomas can be situated at any site in the colon and/or rectum although they tend to be more common in the rectum and distal colon. All of these descriptors, with the exception of number and size, are relatively subjective and subject to interobserver disagreement.

The various descriptive features of adenomas are of value not just to ascertain the neoplastic status of any given adenomas when detected, but also to predict a person's future risk of developing colorectal adenomas or cancer. Those features of an adenoma or number of adenomas in an individual that point to an increased future risk for cancer or recurrence of new adenomas include: size of the largest adenoma (especially 10 mm or larger), degree of villous change (especially at least 25% such change and particularly 100% such change), high grade dysplasia, number (3 or more of any size or histological status) or presence of serrated adenoma features. None except size or number is objective and all are relatively subjective and subject to interobserver disagreement. These predictors of risk for future neoplasia (hence “risk”) are vital in practice because they are used to determine the rate and need for and frequency of future colonoscopic surveillance. More accurate risk classification might thus reduce workload of colonoscopy, make it more cost-effective and reduce the risk of complications from unnecessary procedures.

Adenomas are generally asymptomatic, therefore rendering difficult their diagnosis and treatment at a stage prior to when they might develop invasive characteristics and so became cancer. It is technically impossible to predict the presence or absence of carcinoma based on the gross appearance of adenomas, although larger adenomas are more likely to show a region of malignant change than are smaller adenomas. Sessile adenomas exhibit a higher incidence of malignancy than pedunculated adenomas of the same size. Some adenomas result in blood loss which might be observed or detectable in the stools; while sometimes visible by eye, it is often, when it occurs, microscopic or “occult”. Larger adenomas tend to bleed more than smaller adenomas. However, since blood in the stool, whether overt or occult, can also be indicative of non-adenomatous conditions, the accurate diagnosis of adenoma is rendered difficult without the application of highly invasive procedures such as colonoscopy combined with tissue acquisition by either removal (i.e. polypectomy) or biopsy and subsequent histopathological analysis.

Accordingly, there is an on-going need to elucidate the causes of adenoma and to develop more informative diagnostic protocols or aids to diagnosis that enable one to direct colonoscopy at people more likely to have adenomas. These adenomas may be high risk, advanced or neither of these. Furthermore, it can be difficult after colonoscopy to be certain that all adenomas have been removed, especially in a person who has had multiple adenomas. An accurate screening test may minimise the need to undertake an early second colonoscopy to ensure that the colon has been cleared of neoplasms. Accordingly, the identification of molecular markers for adenomas would provide means for understanding the cause of adenomas and cancer, improving diagnosis of adenomas including development of useful screening tests, elucidating the histological stage of an adenoma, characterising a patient's future risk for colorectal neoplasia on the basis of the molecular state of an adenoma and facilitating treatment of adenomas.

To date, research has focused on the identification of gene mutations which lead to the development of colorectal neoplasms. In work leading up to the present invention, however, it has been determined that changes in expression profiles of genes which are also expressed in healthy individuals are indicative of the development of neoplasms of the large intestine, such as adenomas and adenocarcinomas. It has been further determined that in relation to neoplasms of the large intestine, diagnosis can be made based on screening for one or more of a panel of these differentially expressed genes. In a related aspect, it has still further been determined that to the extent that neoplastic tissue has been identified either by the method of the invention or by some other method, the present invention provides still further means of characterising that tissue as an adenoma or a cancer. In yet another aspect, it has been determined that a proportion of these genes are characterised by gene expression which occurs in the context of a neoplastic state but not in the context of a non-neoplastic state, thereby facilitating the development of qualitative analyses which do not require a relative analysis to be performed against a non-neoplastic or normal control reference level. Accordingly, the inventors have identified a panel of genes which facilitate the diagnosis of adenocarcinoma and adenoma development and/or the monitoring of conditions characterised by the development of these types of neoplasms.

SUMMARY OF THE INVENTION

Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

As used herein, the term “derived from” shall be taken to indicate that a particular integer or group of integers has originated from the species specified, but has not necessarily been obtained directly from the specified source. Further, as used herein the singular forms of “a”, “and” and “the” include plural referents unless the context clearly dictates otherwise.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The subject specification contains amino acid and nucleotide sequence information prepared using the programme PatentIn Version 3.4, presented herein after the bibliography. Each amino acid and nucleotide sequence is identified in the sequence listing by the numeric indicator <210> followed by the sequence identifier (eg. <210>1, <210>2, etc). The length, type of sequence (amino acid, DNA, etc.) and source organism for each sequence is indicated by information provided in the numeric indicator fields <211>m<212> and <213>, respectively. Amino acid and nucleotide sequences referred to in the specification are identified by the indicator SEQ ID NO: followed by the sequence identifier (eg. SEQ ID NO:1, SEQ ID NO: 2, etc). The sequence identifier referred to in the specification correlates to the information provided in numeric indicator field <400> in the sequence listing, which is followed by the sequence identifier (eg. <400>1, <400>2, etc). That is SEQ ID NO: 1 as detailed in the specification correlates to the sequence indicated as <400>1 in the sequence listing.

One aspect of the present invention is directed to a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 201328_at 221577_x_at 205828_at 201341_at 221922_at 205886_at 201416_at 60474_at 205890_s_at 201417_at 222696_at 205910_s_at 201468_s_at 223447_at 205941_s_at 201506_at 223970_at 206224_at 201563_at 225541_at 206976_s_at 201656_at 225835_at 207173_x_at 201925_s_at 226360_at 207457_s_at 201926_s_at 227174_at 208079_s_at 202286_s_at 227475_at 208712_at 202718_at 228303_at 209218_at 202831_at 228653_at 209309_at 202833_s_at 228754_at 209752_at 202935_s_at 228915_at 209773_s_at 202936_s_at 229215_at 209774_x_at 203124_s_at 231832_at 209792_s_at 203256_at 231941_s_at 209875_s_at 203313_s_at 232176_at 209955_s_at 203510_at 232252_at 210052_s_at 203860_at 232481_s_at 210511_s_at 203895_at 234331_s_at 210559_s_at 203896_s_at 235210_s_at 210766_s_at 203961_at 235976_at 211506_s_at 203962_s_at 236894_at 212281_s_at 204259_at 238017_at 212344_at 204351_at 238021_s_at 212353_at 204401_at 238984_at 212354 at 204404_at 241031_at 213905_x_at 204855_at 200660_at 214022_s_at 204885_s_at 200832_s_at 214974_x_at 205174_s_at 200903_s_at 215091_s_at 205366_s_at 201014_s_at 217430_x_at 205470_s_at 201112_s_at 217996_at 205513_at 201195_s_at 218507_at 205765_at 201261_x_at 218963_s_at 205825 at 201292_at 218984_at 205927_s_at 201338_x_at 219787_s_at 205983_at 201479_at 219911_s_at 206239_s_at 201577_at 221729_at 206286_s_at 201601_x_at 221730_at 207158_at 201666_at 221731_x_at 207850_at 202310_s_at 221923_s_at 209369_at 202311_s_at 37892_at 210445_at 202404_s_at 222449_at 210519_s_at 202431_s_at 222450_at 211429_s_at 202504_at 222549_at 212063_at 202779_s_at 222608_s_at 212070_at 202859_x_at 223062_s_at 212190_at 202954_at 224428_s_at 212531_at 202998_s_at 224646_x_at 212942_s_at 203083_at 224915_x_at 213880_at 203213_at 225295_at 213975_s_at 203878_s_at 225520_at 214235_at 204051_s_at 225664_at 214651_s_at 204127_at 225681_at 217523_at 204170_s_at 225767_at 217867_x_at 204320_at 225799_at 218086_at 204470_at 225806_at 218211_s_at 204475_at 226227_x_at 218704_at 204580_at 226237_at 218796_at 204620_s_at 226311_at 218872_at 204702_s_at 226777_at 219630_at 205361_s_at 226835_s_at 219682_s_at 205476_at 227140_at 219727_at 205479_s_at 229802_at 219955_at 205713_s_at 231766_s_at 219956_at 205815_at 232151_at; and/or 200665_s_at (ii) FOXQ1 RNF43 CDCA7 LOXL2 MMP1 CCL20 TDGF1 AZGP1 TCN1 CTSE MTHFD1L MYC MMP7 MSLN ANLN COMP WDR72 TIMP1 H19 AURKA INHBA PCSK1 FAP PAICS COL11A1 CST1 DACH1 PUS7 GDF15 BGN VCAN ZNRF3 CTHRC1 AXIN2 SQLE CCND1 COL1A1 MET REG3A CSE1L LGR5 SOX9 TESC PFDN4 DUSP27 TMEPAI UBE2C C20orf42 SERPINB5 CDH11 TMEM97 SLC11A2 ASCL2 MMP11 TRIM29 NFE2L3 SULF1 CXCL1 KLK11 CEL SLC6A6 QPCT LY6G6D NLF1 TACSTD2 PDZK1IP1 SLC7A5 NPDC1 NEBL CD55 FABP6 ENC1 PCCA ECT2 SLITRK6 SERPINE2 FLJ37644 COL12A1 MLPH UBE2S KRT23 L1TD1 HOXA9 TOP2A CXCL3 WDR51B TBX3 CDC2 MMP3 HOXB6 BACE2 RFC3 SFRP4 FAM84A GPX2 LILRB1 UBD COL5A2 TPX2 NPM1 SCD MMP12 KCNN4 RDHE2 DPEP1 SORD LOC541471 PLAU LCN2 PSAT1 CYP3A5 HSPH1 PLCB4 CXCL5 ANXA3 GTF3A SPUNK1 IGFBP2 CYP3A5P2 KLK10 DUOX2 TGIF1 C14orf94 GPSM2 SOX4 CXCL2 RP5-875H10.1 NME1 THBS2 SLCO4A1 RPL22L1 MUC20 CLDN1 CKS2 APOBEC1 RPESP REG1B PHLDA1 HIG2 RRM2 CDH3 SERPINA1 COL10A1 DKC1 SPARC COL1A2 AHCY CD44 IL8 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to control levels is indicative of a neoplastic large intestine cell or a cell predisposed to the onset of a neoplastic state.

In another aspect there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix         probeset IDs: 225681_at; 227140_at; and/or     -   (ii) CTHRC1         in a biological sample from said individual wherein a higher         level of expression of the genes or transcripts of group (i)         and/or group (ii) relative to control levels is indicative of a         neoplastic large intestine cell or a cell predisposed to the         onset of a neoplastic state.

In yet another aspect there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix         probeset IDs:         -   227475_at         -   204475_at         -   202859_x_at         -   202404_s_at; and/or     -   (ii) FOXQ1, MMP1, IL8, COL1A2         in a biological sample from said individual wherein a higher         level of expression of the genes or transcripts of group (i)         and/or group (ii) relative to control levels is indicative of a         neoplastic large intestine cell or a cell predisposed to the         onset of a neoplastic state.

In still another aspect there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix         probeset IDs:         -   205513_at, 204259_at, 227174_at, 210511_s_at, 37892_at;             and/or     -   (ii) TCN1, MMP7, WDR72, INHBA, COL11A1         in a biological sample from said individual wherein a higher         level of expression of the genes or transcripts of group (i)         and/or group (ii) relative to control levels is indicative of a         neoplastic large intestine cell or a cell predisposed to the         onset of a neoplastic state.

Preferably, said control level is a non-neoplastic level.

In still yet another aspect there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 221577_x_at 212942_s_at 202310_s_at 213880_at 232252_at 204855_at 229215_at 212354_at 228754_at 202286_s_at 203962_s_at 203860_at 202935_s_at 218963_s_at 207850_at 205828_at 204051_s_at 205890_s_at 200832_s_at 205983_at 212531_at; and/or (ii) LGR5 GDF15 COL1A1 ASCL2 DUSP27 SERPINB5 TACSTD2 SULF1 SLC6A6 FLJ37644 NEBL PCCA MMP3 KRT23 CXCL3 SCD SFRP4 UBD DPEP1 LCN2 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to control levels is indicative of a neoplastic large intestine cell or a cell predisposed to the onset of a neoplastic state.

In a further aspect the present invention is directed to a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 201328_at 205825_at 219956_at 201468_s_at 205927_s_at 221922_at 201656_at 206239_s_at 223447_at 201925_s_at 207158_at 223970_at 201926_s_at 210445_at 225835_at 202718_at 210519_s_at 226360_at 202831_at 211429_s_at 228303_at 202833_s_at 212063_at 228653_at 203124_s_at 213975_s_at 228915_at 203313_s_at 214235_at 231832_at 203860_at 214651_s_at 231941_s_at 203895_at 217523_at 232176_at 203896_s_at 217867_x_at 232481_s_at 204401_at 218086_at 234331_s_at 204885_s_at 218211_s_at 235210_s_at 205174_s_at 218796_at 235976_at 205366_s_at 219630_at 236894_at 205470_s_at 219682_s_at 238017_at 205513_at 219727_at 238984_at 205765_at 219955_at; 241031_at; and/or (ii) APOBEC1 HOXB6 QPCT BACE2 IGFBP2 RDHE2 C20orf42 ITGA6 REG4 CD44 KCNN4 RETNLB CD55 KLK11 RP5-875H10.1 CTSE LITD1 RPESP CYP3A5 LILRB1 SERPINA1 CYP3A5P2 MLPH SLC11A2 DACH1 MSLN SLC12A2 DUOX2 MUC20 SLITRK6 ETS2 NLF1 SPINK1 FABP6 NPDC1 TBX3 FAM84A NQO1 TCN1 GALNT6 PCCA TGIF1 GPSM2 PCSK1 WDR51B GPX2 PDZK1IP1 ZNRF3 HOXA9 PLCB4 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to control levels is indicative of an adenoma cell or a cell predisposed to the onset of an adenoma state.

In another further aspect of the present invention there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 200660_at 205476_at 217430_x_at 200665_s_at 205479_s_at 217996_at 200832_s_at 205713_s_at 218507_at 200903_s_at 205815_at 218963_s_at 201014_s_at 205828_at 218984_at 201112_s_at 205886_at 219787_s_at 201195_s_at 205890_s_at 219911_s_at 201261_x_at 205910_s_at 221729_at 201292_at 205941_s_at 221730_at 201338_x_at 206224_at 221731_x_at 201479_at 206976_s_at 221923_s_at 201577_at 207173_x_at 37892_at 201601_x_at 207457_s_at 222449_at 201666_at 208079_s_at 222450_at 202310_s_at 208712_at 222549_at 202311_s_at 209218_at 222608_s_at 202403_s_at 209309_at 223062_s_at 202404_s_at 209752_at 224428_s_at 202431_s_at 209773_s_at 224646_x_at 202504_at 209774_x_at 224915_x_at 202779_s_at 209792_s_at 225295_at 202859_x_at 209875_s_at 225520_at 202954_at 209955_s_at 225664_at 202998_s_at 210052_s_at 225681_at 203083_at 210511_s_at 225767_at 203213_at 210559_s_at 225799_at 203878_s_at 210766_s_at 225806_at 204051_s_at 211506_s_at 226227_x_at 204127_at 212281_s_at 226237_at 204170_s_at 212344_at 226311_at 204320_at 212353_at 226777_at 204470_at 212354_at 226835_s_at 204475_at 213905_x_at 227140_at 204580_at 214022_s_at 229802_at 204620_s_at 214974_x_at 231766_s_at 204702_s_at 215091_s_at; 232151_at; and/or 205361_s_at (ii) AHCY DKC1 PSAT1 ANLN ECT2 PUS7 AURKA FAP REG1A AZGP1 GTF3A REG1B BGN H19 REG3A C14orf94 HIG2 RFC3 C20orf199 HSPH1 RRM2 CCL20 IFITM1 S100A11 CCND1 IL8 SCD CDC2 INHBA SFRP4 CDCA7 KLK10 SLC39A10 CDH11 KRT23 SLC7A5 CEL LOC541471 SLC04A1 CKS2 LOXL2 SPARC CLDN1 LY6G6D SPP1 COL10A1 MMP1 SQLE COL11A1 MMP11 SULF1 COL12A1 MMP12 THBS2 COL1A1 MMP3 TIMP1 COL1A2 MTHFD1L TMEM97 COL5A2 MYC TMEPAI COL8A1 NFE2L3 TOP2A COMP NME1 TPX2 CSE1L NPM1 TRIM29 CST1 PAICS UBD CTHRC1 PFDN4 UBE2C CXCL1 PHLDA1 UBE2S CXCL2 PLAU VCAN CXCL5 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to control levels is indicative of a cancer cell or a cell predisposed to the onset of a cancerous state.

In yet another further aspect there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 202286_s_at 235976_at 209309_at 204259_at 236894_at 211506_s_at 204885_s_at 214974_x_at 205174_s_at 238984_at 219787_s_at 205825_at 241031_at 37892_at 207850_at 202311_s_at 222608_s_at 213880_at 204320_at 223062_s_at 217523_at 204475_at 225806_at 227174_at 204702_s_at 226237_at 228915_at 205910_s_at 227140_at 232252_at 206224_at 229802_at; and/or (ii) MMP1 PCSK1 ANLN MMP7 CST1 DACH1 LGR5 QPCT COL11A1 WDR72 ECT2 C14orf94 COL11A1 SLITRK6 AZGP1 COL1A1 LITD1 REG4 DUSP27 KIAA1199 NFE2L3 NLF1 PSAT1 CEL IL8 CXCL5 CD44 TACSTD2 CXCL3 COL8A1 MSLN in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to background levels is indicative of a neoplastic cell or a cell predisposed to the onset of a neoplastic state.

Yet another aspect of the present invention provides a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 204885_s_at 217523_at 236894_at 205174_s_at 228915_at 238984_at 205825_at 235976_at 241031_at; and/or (ii) CD44 MSLN QPCT DACH1 NLF1 REG4 L1TD1 PCSK1 SLITRK6 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to background levels is indicative of an adenoma cell or a cell predisposed to the onset of an adenoma state.

In yet still another aspect there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene or genes detected by Affymetrix probeset IDs: (i) 202311_s_at 209309_at 223062_s_at 204320_at 211506_s_at 225806_at 204475_at 214974_x_at 226237_at 204702_s_at 219787_s_at 227140_at 205910_s_at 37892_at 229802_at; and/or 206224_at 222608_s_at (ii) ANLN COL1A1 IL8 AZGP1 COL8A1 MMP1 C14orf94 CST1 NFE2L3 CEL CXCL5 PSAT1 COL11A1 ECT2 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to background levels is indicative of a cancer cell or a cell predisposed to the onset of a cancerous state.

In still yet another aspect of the present invention, there is provided a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 200884_at 214234_s_at 226248_s_at 203240_at 214235_at 226302_at 203963_at 214433_s_at 227676_at 204508_s_at 215125_s_at 227719_at 204607_at 215867_x_at 227725_at 204811_s_at 217109_at 228232_s_at 204895_x_at 217110_s_at 229070_at 204897_at 218211_s_at 231832_at 205259_at 219543_at 232176_at 205765_at 219955_at 232481_s_at 205927_s_at 221841_s_at 235976_at 208063_s_at 221874_at 236894_at 208937_s_at 223969_s_at 237521_x_at 210107_at 223970_at 242601_at 213106_at; and/or (ii) CLCA1 CTSE ATP8B1 FCGBP C6orf105 CACNA2D2 HMGCS2 CKB KLF4 RETNLB ATP8A1 CYP3A5P2 L1TD1 MUC4 CAPN9 SLITRK6 UGT1A1 NR3C2 VSIG2 SELENBP1 PBLD LOC253012 PTGER4 CA12 ST6GALNAC1 MLPH WDR51B ID1 KIAA1324 FAM3D CYP3A5 in said cell or cellular population wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to a gastrointestinal cancer cell level is indicative of an adenoma cell or a cell predisposed to the onset of an adenoma state.

In another aspect there is provided a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 200600_at 204006_s_at 213428_s_at 200665_s_at 204051_s_at 213524_s_at 200832_s_at 204122_at 213869_x_at 200974_at 204320_at 213905_x_at 200986_at 204475_at 214247_s_at 201058_s_at 204620_s_at 215049_x_at 201069_at 205479_s_at 215076_s_at 201105_at 205547_s_at 215646_s_at 201141_at 205828_at 216442_x_at 201147_s_at 207173_x_at 217430_x_at 201150_s_at 207191_s_at 217762_s_at 201162_at 208747_s_at 217763_s_at 201163_s_at 208782_at 217764_s_at 201185_at 208788_at 218468_s_at 201261_x_at 208850_s_at 218469_at 201289_at 208851_s_at 218559_s_at 201426_s_at 209101_at 218638_s_at 201438_at 209156_s_at 219087_at 201616_s_at 209218_at 221011_s_at 201645_at 209395_at 221729_at 201667_at 209396_s_at 221730_at 201744_s_at 209596_at 221731_x_at 201792_at 209875_s_at 37892_at 201842_s_at 209955_s_at 223122_s_at 201852_x_at 210095_s_at 223235_s_at 201859_at 210495_x_at 224560_at 201893_x_at 210511_s_at 224694_at 202237_at 210764_s_at 224724_at 202238_s_at 210809_s_at 225664_at 202283_at 211161_s_at 225681_at 202291_s_at 211571_s_at 225710_at 202310_s_at 211719_x_at 225799_at 202311_s_at 211813_x_at 226237_at 202403_s_at 211896_s_at 226311_at 202404_s_at 211959_at 226694_at 202450_s_at 211964_at 226777_at 202620_s_at 211966_at 226930_at 202766_s_at 211980_at 227099_s_at 202859_x_at 211981_at 227140_at 202878_s_at 212077_at 227566_at 202917_s_at 212344_at 229218_at 202998_s_at 212353_at 229802_at 203083_at 212354_at 231579_s_at 203325_s_at 212464_s_at 231766_s_at 203382_s_at 212488_at 231879_at 203477_at 212489_at 232458_at 203570_at 212667_at 233555_s_at 203645_s_at 213125_at 234994_at 203878_s_at; and/or (ii) COL1A2 LGALS1 SRGN CTHRC1 ELOVL5 LBH FN1 MGP CTGF POSTN MMP2 TNC SPP1 LOXL2 G0S2 MMP1 MYL9 SQLE SPARC DCN EFEMP1 LUM CALD1 APOE GREM1 FBN1 MSN IL8 MMP3 IGFBP3 IGFBP5 IGFBP7 SERPINF1 SFRP2 FSTL1 ISLR SULF1 COL4A2 HNT ASPN VCAN COL5A1 COL6A3 SMOC2 OLFML2B COL5A1 HTRA1 KIAA1913 COL12A1 CYR61 PALM2-AKAP2 COL5A2 FAP SERPING1 CDH11 VIM TYROBP THBS2 TIMP2 ACTA2 COL15A1 SCD COL3A1 COL11A1 TIMP3 PLOD2 S100A8 AEBP1 MMP11 FNDC1 GJA1 CD163 SFRP4 NNMT FCGR3B INHBA COL1A1 PLAU COL6A2 SULF2 MAFB ANTXR1 COL6A1 LOC541471 GPNMB SPON2 LOC387763 BGN CTSK CHI3L1 TAGLN MXRA5 THY1 COL4A1 CIS LOXL1 RAB31 DKK3 CD93 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to a gastrointestinal adenoma cell level is indicative of a cancer or a cell predisposed to the onset of a cancerous state.

In a further aspect there is provided a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

-   -   (i) the gene or genes detected by Affymetrix probeset IDs:         -   210107_at; and/or     -   (ii) CLCA1         in a biological sample from said individual wherein a higher         level of expression of the genes or transcripts of group (i)         and/or group (ii) relative to a gastrointestinal cancer control         level is indicative of an adenoma cell or a cell predisposed to         the onset of an adenoma state.

In another aspect there is provided a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 203240_at 219955_at 242601_at 204607_at 232481_s_at 227725_at 223969_s_at 228232_s_at; and/or (ii) FCGBP L1TD1 LOC253012 HMGCS2 SLITRK6 ST6GALNAC1 RETNLB VSIG2 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to a gastrointestinal cancer control level is indicative of an adenoma cell or a cell predisposed to the onset of an adenoma state.

A further aspect of the present invention is directed to a method of characterising a cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix         probeset IDs:         -   202404_s_at, 210809_s_at, 227140_at, 225681_at, 209875_s_at,             204475_at, 212464_s_at; and/or,

(ii) COL1A2, FN1, SPP1, CTHRC1, POSTN, MMP1

in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or (ii) relative to a gastrointestinal adenoma control level is indicative of a cancer or a cell predisposed to the onset of a cancerous state.

In yet another further aspect the present invention is directed to a method of characterising a cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix         probeset IDs:         -   200665_s_at, 218468_s_at, 211959_at, 201744_s_at,             202859_x_at; and/or,     -   (ii) SPARC, GREM1, IGFBP5, LUM, IL8,         in a biological sample from said individual wherein a higher         level of expression of the genes or transcripts of group (i)         and/or (ii) relative to a gastrointestinal adenoma control level         is indicative of a cancer or a cell predisposed to the onset of         a cancerous state.

In still yet another further aspect the present invention is directed to a method of characterising a cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 223122_s_at 207173_x_at 210511_s_at 212353_at 203083_at 209156_s_at 219087_at 203477_at 224694_at 201438_at 37892_at 201141_at 226237_at 202917_s_at 213905_x_at 225664_at 226930_at 205547_s_at 221730_at 204051_s_at; and/or (ii) SFRP2 CDH11 INHBA SULF1 THBS2 COL6A2 ASPN COL15A1 ANTXR1 COL6A3 COL11A1 GPNMB COL8A1 S100A8 BGN COL12A1 FNDC1 TAGLN COL5A2 SFRP4 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or (ii) relative to a gastrointestinal adenoma control level is indicative of a cancer or a cell predisposed to the onset of a cancerous state.

Yet another aspect of the present invention provides a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 235976_at 236894_at; and/or (ii) SLITRK6 L1TD1 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or (ii) relative to neoplastic tissue background levels is indicative of an adenoma cell or a cell predisposed to the onset of an adenoma state.

In still another aspect the present invention provides a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix         probeset IDs:         -   202311_s_at, 209396_s_at, 226237_at, 204320_at, 215646_s_at,             227140_at, 204475_at, 37892_at, 229802_at, 209395_at; and/or     -   (ii) COL1A1, VCAN, CHI3L1, MMP1, COL8A1, COL11A1         in a biological sample from said individual wherein a higher         level of expression of the genes or transcripts of group (i)         and/or (ii) relative to neoplastic tissue background neoplastic         cell levels is indicative of a cancer or a cell predisposed to         the onset of a cancerous state.

A related aspect of the present invention provides a molecular array, which array comprises a plurality of:

-   (i) nucleic acid molecules comprising a nucleotide sequence     corresponding to any one or more of the neoplastic marker genes     hereinbefore described or a sequence exhibiting at least 80%     identity thereto or a functional derivative, fragment, variant or     homologue of said nucleic acid molecule; or -   (ii) nucleic acid molecules comprising a nucleotide sequence capable     of hybridising to any one or more of the sequences of (i) under     medium stringency conditions or a functional derivative, fragment,     variant or homologue of said nucleic acid molecule; or -   (iii) nucleic acid probes or oligonucleotides comprising a     nucleotide sequence capable of hybridising to any one or more of the     sequences of (i) under medium stringency conditions or a functional     derivative, fragment, variant or homologue of said nucleic acid     molecule; or -   (iv) probes capable of binding to any one or more of the proteins     encoded by the nucleic acid molecules of (i) or a derivative,     fragment or, homologue thereof     wherein the level of expression of said marker genes of (i) or     proteins of (iv) is indicative of the neoplastic state of a cell or     cellular subpopulation derived from the large intestine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of nuclear factor (erythroid-derived-2)-like 2. Blk=normal, grn=inflamed, red=adenoma, blue=cancer

FIG. 2 is a graphical representation of SLIT and NTRK-like family, member 6 (left) and LINE1 type transposase domain containing 1 (right).

FIG. 3 is a graphical representation of collagen type XI, alpha 1.

FIG. 4 is an image of the immunohistochemical staining for MSLN in a normal tissue shows mild staining in the cytoplasm of the colonocytes.

FIG. 5 is an image of the immunohistochemical staining for MSLN in a representative cancer tissue shows moderate staining in the cytoplasm of the colonic epithelia.

FIG. 6 is an image of the immunohistochemical staining of MSLN in a moderately differentiated adenoma shows strong staining in the multilayered colonic epithelium.

FIG. 7 is a graphical representation depicting Probeset 205828 at Expression profile across 68 clinical specimens comprising 30 non-disease controls (black), 19 adenomas (red) and 19 adenocarcinoma (green).

FIG. 8 is a graphical representation of the measurement of MMP3 expression in protein extract from 27 clinical stool specimens. Protein extraction was performed on 27 clinical stool specimens comprising 6 non-disease controls (circle), 10 adenoma (triangle) and 11 adenocarcinoma (cross) emulsified using a PBS pH 7.4 solution containing 0.05% Tween-20 and 1× Protease Inhibitor Cocktail (Roche). Proteins were further solubilised by 30 minutes incubation in an ultrasonic water bath. Solubilised proteins were isolated by centrifugation and endogenous levels of MMP3 in the resulting protein extracts were using measured using a commercially available Luminex bead-based suspension immunoassay as recommended by manufacturer (R&D Systems).

FIG. 9 is a graphical representation of Affymetrix probeset ID 205828 at which is known to hybrising to transcripts of the MMP3 gene depicting a gene expression profile in 68 clinical specimens comprising 30 non-disease controls (black), 19 adenomas (red) and 19 cancers (green).

FIG. 10 is a schematic representation of predicted RNA variants derived from hCG_(—) 1815491. cDNA clones derived from map region 8579310 to 8562303 on human chromosome 16 were used to locate exon sequences. Arrows: Oligo nucleotide primer sets were designed to allow measurement of individual RNA variants by PCR. Primers covering splice junctions are shown as spanning intron sequences which is not included in the actual oligonucleotide primer sequence.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is predicated, in part, on the elucidation of gene expression profiles which characterise large intestine cellular populations in terms of their neoplastic state and, more particularly, whether they are malignant or pre-malignant. This finding has now facilitated the development of routine means of screening for the onset or predisposition to the onset of a large intestine neoplasm or characterising cellular populations derived from the large intestine based on screening for upregulation of the expression of these molecules, relative to control expression patterns and levels. To this end, in addition to assessing expression levels of the subject genes relative to normal or non-neoplastic levels, it has been determined that a proportion of these genes are expressed only in the diseased state, thereby facilitating the development of a simple qualitative test based on requiring assessment only relative to test background levels.

In accordance with the present invention, it has been determined that the genes detailed above are modulated, in terms of differential changes to their levels of expression, depending on whether the cell expressing that gene is neoplastic or not. It should be understood that reference to a gene “expression product” or “expression of a gene” is a reference to either a transcription product (such as primary RNA or mRNA) or a translation product such as protein. These genes and their expression products, whether they be RNA transcripts or encoded proteins, are collectively referred to as “neoplastic markers”.

Accordingly, one aspect of the present invention is directed to a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 201328_at 221577_x_at 205828_at 201341_at 221922_at 205886_at 201416_at 60474_at 205890_s_at 201417_at 222696_at 205910_s_at 201468_s_at 223447_at 205941_s_at 201506_at 223970_at 206224_at 201563_at 225541_at 206976_s_at 201656_at 225835_at 207173_x_at 201925_s_at 226360_at 207457_s_at 201926_s_at 227174_at 208079_s_at 202286_s_at 227475_at 208712_at 202718_at 228303_at 209218_at 202831_at 228653_at 209309_at 202833_s_at 228754_at 209752_at 202935_s_at 228915_at 209773_s_at 202936_s_at 229215_at 209774_x_at 203124_s_at 231832_at 209792_s_at 203256_at 231941_s_at 209875_s_at 203313_s_at 232176_at 209955_s_at 203510_at 232252_at 210052_s_at 203860_at 232481_s_at 210511_s_at 203895_at 234331_s_at 210559_s_at 203896_s_at 235210_s_at 210766_s_at 203961_at 235976_at 211506_s_at 203962_s_at 236894_at 212281_s_at 204259_at 238017_at 212344_at 204351_at 238021_s_at 212353_at 204401_at 238984_at 212354_at 204404_at 241031_at 213905_x_at 204855_at 200660_at 214022_s_at 204885_s_at 200832_s_at 214974_x_at 205174_s_at 200903_s_at 215091_s_at 205366_s_at 201014_s_at 217430_x_at 205470_s_at 201112_s_at 217996_at 205513_at 201195_s_at 218507_at 205765_at 201261_x_at 218963_s_at 205825_at 201292_at 218984_at 205927_s_at 201338_x_at 219787_s_at 205983_at 201479_at 219911_s_at 206239_s_at 201577_at 221729_at 206286_s_at 201601_x_at 221730_at 207158_at 201666_at 221731_x_at 207850_at 202310_s_at 221923_s_at 209369_at 202311_s_at 37892_at 210445_at 202404_s_at 222449_at 210519_s_at 202431_s_at 222450_at 211429_s_at 202504_at 222549_at 212063_at 202779_s_at 222608_s_at 212070_at 202859_x_at 223062_s_at 212190_at 202954_at 224428_s_at 212531_at 202998_s_at 224646_x_at 212942_s_at 203083_at 224915_x_at 213880_at 203213_at 225295_at 213975_s_at 203878_s_at 225520_at 214235_at 204051_s_at 225664_at 214651_s_at 204127_at 225681_at 217523_at 204170_s_at 225767_at 217867_x_at 204320_at 225799_at 218086_at 204470_at 225806_at 218211_s_at 204475_at 226227_x_at 218704_at 204580_at 226237_at 218796_at 204620_s_at 226311_at 218872_at 204702_s_at 226777_at 219630_at 205361_s_at 226835_s_at 219682_s_at 205476_at 227140_at 219727_at 205479_s_at 229802_at 219955_at 205713_s_at 231766_s_at 219956_at 205815_at 232151_at; and/or 200665_s_at (ii) CTHRC1 CDCA7 LOXL2 FOXQ1 RNF43 TDGF1 AZGP1 MMP1 CCL20 MTHFD1L MYC TCN1 CTSE ANLN COMP MMP7 MSLN H19 AURKA WDR72 TIMP1 FAP PAICS INHBA PCSK1 DACH1 PUS7 COL11A1 CST1 VCAN ZNRF3 GDF15 BGN SQLE CCND1 COL1A1 AXIN2 REG3A CSE1L LGR5 MET TESC PFDN4 DUSP27 SOX9 UBE2C C20orf42 SERPINB5 TMEPAI TMEM97 SLC11A2 ASCL2 CDH11 TRIM29 NFE2L3 SULF1 MMP11 KLK11 CEL SLC6A6 CXCL1 LY6G6D NLF1 TACSTD2 QPCT SLC7A5 NPDC1 NEBL PDZK1IP1 FABP6 ENC1 PCCA CD55 SLITRK6 SERPINE2 FLJ37644 ECT2 MLPH UBE2S KRT23 COL12A1 HOXA9 TOP2A CXCL3 L1TD1 TBX3 CDC2 MMP3 WDR51B BACE2 RFC3 SFRP4 HOXB6 GPX2 LILRB1 UBD FAM84A TPX2 NPM1 SCD COL5A2 KCNN4 RDHE2 DPEP1 MMP12 LOC541471 PLAU LCN2 SORD CYP3A5 HSPH1 PLCB4 PSAT1 ANXA3 GTF3A SPINK1 CXCL5 CYP3A5P2 KLK10 DUOX2 IGFBP2 C14orf94 GPSM2 SOX4 TGIF1 RP5-875H10.1 NME1 THBS2 CXCL2 RPL22L1 MUC20 CLDN1 SLCO4A1 APOBEC1 RPESP REG1B CKS2 HIG2 RRM2 CDH3 PHLDA1 COL10A1 DKC1 SPARC SERPINA1 AHCY CD44 COL1A2 IL8 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to control levels is indicative of a neoplastic large intestine cell or a cell predisposed to the onset of a neoplastic state.

Reference to “large intestine” should be understood as a reference to a cell derived from one of the six anatomical regions of the large intestine, which regions commence after the terminal region of the ileum, these being:

-   -   (i) the cecum;     -   (ii) the ascending colon;     -   (iii) the transverse colon;     -   (iv) the descending colon;     -   (v) the sigmoid colon; and     -   (vi) the rectum.

Reference to “neoplasm” should be understood as a reference to a lesion, tumour or other encapsulated or unencapsulated mass or other form of growth which comprises neoplastic cells. A “neoplastic cell” should be understood as a reference to a cell exhibiting abnormal growth. The term “growth” should be understood in its broadest sense and includes reference to proliferation. In this regard, an example of abnormal cell growth is the uncontrolled proliferation of a cell. Another example is failed apoptosis in a cell, thus prolonging its usual life span. The neoplastic cell may be a benign cell or a malignant cell. In a preferred embodiment, the subject neoplasm is an adenoma or an adenocarcinoma. Without limiting the present invention to any one theory or mode of action, an adenoma is generally a benign tumour of epithelial origin which is either derived from epithelial tissue or exhibits clearly defined epithelial structures. These structures may take on a glandular appearance. It can comprise a malignant cell population within the adenoma, such as occurs with the progression of a benign adenoma to a malignant adenocarcinoma.

Preferably, said neoplastic cell is an adenoma or adenocarcinoma and even more preferably a colorectal adenoma or adenocarcinoma.

Each of the genes and transcripts detailed in sub-paragraphs (i) and (ii), above, would be well known to the person of skill in the art, as would their encoded proteins. The identification of the expression products of these genes and transcripts as markers of neoplasia occurred by virtue of differential expression analysis using Affymetrix HGU133Aor HGU133B gene chips. To this end, each gene chip is characterised by approximately 45,000 probe sets which detect the RNA transcribed from the genome. On average, approximately 11 probe pairs detect overlapping or consecutive regions of the RNA transcript. In general, the genes from which the RNA transcripts described herein are identified by the Affymetrix probesets are well known and characterised genes. However, to the extent that some of the probesets detect RNA transcripts which are not yet defined, these transcripts are indicated as “the gene, genes or transcripts detected by Affymetrix probe x”. In some cases a number of genes and/or transcripts may be detectable by a single probeset. It should be understood, however, that this is not intended as a limitation as to how the expression level of the subject gene or transcript can be detected. In the first instance, it would be understood that the subject gene transcript is also detectable by other probesets which would be present on the Affymetrix gene chip. The reference to a single probesets is merely included as an identifier of the gene transcript of interest. In terms of actually screening for the transcript, however, one may utilise a probe or probeset directed to any region of the transcript and not just to the 3′ terminal 600 bp transcript region to which the Affymetrix probesets are often directed.

Reference to each of the genes and transcripts detailed above and their transcribed and translated expression products should therefore be understood as a reference to all forms of these molecules and to fragments or variants thereof. As would be appreciated by the person of skill in the art, some genes are known to exhibit allelic variation between individuals. Accordingly, the present invention should be understood to extend to such variants which, in terms of the present diagnostic applications, achieve the same outcome despite the fact that minor genetic variants between the actual nucleic acid sequences may exist between individuals or that within one individual there may exist two or more splice variants of one subject gene. The present invention should therefore be understood to extend to all forms of RNA (eg mRNA, primary RNA transcript, miRNA, etc), cDNA and peptide isoforms which arise from alternative splicing or any other mutation, polymorphic or allelic variation. It should also be understood to include reference to any subunit polypeptides such as precursor forms which may be generated, whether existing as a monomer, multimer, fusion protein or other complex.

For example, in one embodiment of the invention, the subject gene is CDH3. Analysis of the AceView Database reveals that there exist 12 CDH3 alternative mRNA transcripts. Nine are generated by alternative splicing while three are unspliced forms. In terms of the genes encompassed by the present invention, means for determining the existence of such variants and characterising same, are described in Example 6. To the extent that the genes of the present invention are described by reference to an Affymetrix probeset, Table 9 provides details of the nucleic acid sequence to which each probeset is directed. Based on this information, the skilled person could, as a matter of routine procedure, identify the gene in respect of which that sequence forms part. A typical protocol for doing this is also outlined in Example 6.

It should be understood that the “individual” who is the subject of testing may be any human or non-human mammal. Examples of non-human mammals includes primates, livestock animals (e.g. horses, cattle, sheep, pigs, donkeys), laboratory test animals (e.g. mice, rats, rabbits, guinea pigs), companion animals (e.g. dogs, cats) and captive wild animals (e.g. deer, foxes). Preferably the mammal is a human.

The method of the present invention is predicated on the comparison of the level of the neoplastic markers of a biological sample with the control levels of these markers. The “control level” may be either a “normal level”, which is the level of marker expressed by a corresponding large intestine cell or cellular population which is not neoplastic, or the background level which is detectable in a negative control sample.

The normal (or “non-neoplastic”) level may be determined using tissues derived from the same individual who is the subject of testing. However, it would be appreciated that this may be quite invasive for the individual concerned and it is therefore likely to be more convenient to analyse the test results relative to a standard result which reflects individual or collective results obtained from individuals other than the patient in issue. This latter form of analysis is in fact the preferred method of analysis since it enables the design of kits which require the collection and analysis of a single biological sample, being a test sample of interest. The standard results which provide the normal level may be calculated by any suitable means which would be well known to the person of skill in the art. For example, a population of normal tissues can be assessed in terms of the level of the neoplastic markers of the present invention, thereby providing a standard value or range of values against which all future test samples are analysed. It should also be understood that the normal level may be determined from the subjects of a specific cohort and for use with respect to test samples derived from that cohort. Accordingly, there may be determined a number of standard values or ranges which correspond to cohorts which differ in respect of characteristics such as age, gender, ethnicity or health status. Said “normal level” may be a discrete level or a range of levels. An increase in the expression level of the subject genes relative to normal levels is indicative of the tissue being neoplastic.

Without limiting the present invention to any one theory or mode of action, although each of the genes hereinbefore described is differentially expressed, either singly or in combination, as between neoplastic versus non-neoplastic cells of the large intestine, and is therefore diagnostic of the existence of a large intestine neoplasm, the expression of some of these genes was found to exhibit particularly significant levels of sensitivity, specificity and positive and negative predictive value. Accordingly, in a preferred embodiment one would screen for and assess the expression level of one or more of these genes. To this end, and without limiting the present invention to any one theory or mode of action, the following markers were determined to be expressed in neoplastic tissue at a level of 3, 4, 5 or 7 fold greater than non-neoplastic tissue when assessed by virtue of the method exemplified herein.

Fold Gene, genes or transcripts Increase detected by Affymetrix Probe No: Gene 7 225681_at CTHRC1 227140_at 5 227475_at FOXQ1 204475_at MMP1 202859_x_at IL8 202404_s_at COL1A2 4 205513_at TCN1 204259_at MMP7 227174_at WDR72 210511_s_at INHBA 37892_at COL11A1 3 221577_x_at GDF15 202310_s_at COL1A1 213880_at LGR5 232252_at DUSP27 204855_at SERPINB5 229215_at ASCL2 212354_at SULF1 228754_at SLC6A6 202286_s_at TACSTD2 203962_s_at NEBL 203860_at PCCA 202935_s_at FLJ37644 218963_s_at KRT23 207850_at CXCL3 205828_at MMP3 204051_s_at SFRP4 205890_s_at UBD 200832_s_at SCD 205983_at DPEP1 212531_at LCN2

There is therefore more particularly provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix         probeset IDs:         -   225681_at; 227140_at; and/or     -   (ii) CTHRC1         in a biological sample from said individual wherein a higher         level of expression of the genes or transcripts of group (i)         and/or group (ii) relative to control levels is indicative of a         neoplastic large intestine cell or a cell predisposed to the         onset of a neoplastic state.

Preferably, said control level is a non-neoplastic level.

In another embodiment, there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix         probeset IDs:         -   227475_at, 204475_at, 202859_x_at, 202404_s_at; and/or     -   (ii) FOXQ1, MMP1, IL8, COL1A2         in a biological sample from said individual wherein a higher         level of expression of the genes or transcripts of group (i)         and/or group (ii) relative to control levels is indicative of a         neoplastic large intestine cell or a cell predisposed to the         onset of a neoplastic state.

Preferably, said control level is a non-neoplastic level.

In yet another embodiment there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix         probeset IDs: 205513_at, 204259_at, 227174_at, 210511_s_at,         37892_at; and/or     -   (ii) TCN1, MMPI, WDR72, INHBA, COL11A1         in a biological sample from said individual wherein a higher         level of expression of the genes or transcripts of group (i)         and/or group (ii) relative to control levels is indicative of a         neoplastic large intestine cell or a cell predisposed to the         onset of a neoplastic state.

Preferably, said control level is a non-neoplastic level.

In still yet another preferred embodiment, there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 221577_x_at 232252_at 202310_s_at 213880_at 212354_at 204855_at 229215_at 203962_s_at 228754_at 202286_s_at 218963_s_at 203860_at 202935_s_at 204051_s_at 207850_at 205828_at 205983_at 205890_s_at 200832_s_at 212531_at; and/or (ii) LGR5 GDF15 COL1A1 ASCL2 DUSP27 SERPINB5 TACSTD2 SULF1 SLC6A6 FLJ37644 NEBL PCCA MMP3 KRT23 CXCL3 SCD SFRP4 UBD DPEP1 LCN2 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to control levels is indicative of a neoplastic large intestine cell or a cell predisposed to the onset of a neoplastic state.

Preferably, said control level is a non-neoplastic level.

According to these aspects of the present invention, said large intestine tissue is preferably colorectal tissue.

The detection method of the present invention can be performed on any suitable biological sample. To this end, reference to a “biological sample” should be understood as a reference to any sample of biological material derived from an animal such as, but not limited to, cellular material, biofluids (eg. blood), faeces, tissue biopsy specimens, surgical specimens or fluid which has been introduced into the body of an animal and subsequently removed (such as, for example, the solution retrieved from an enema wash). The biological sample which is tested according to the method of the present invention may be tested directly or may require some form of treatment prior to testing. For example, a biopsy or surgical sample may require homogenisation prior to testing or it may require sectioning for in situ testing of the qualitative expression levels of individual genes. Alternatively, a cell sample may require permeabilisation prior to testing. Further, to the extent that the biological sample is not in liquid form, (if such form is required for testing) it may require the addition of a reagent, such as a buffer, to mobilise the sample.

To the extent that the neoplastic marker gene expression product is present in a biological sample, the biological sample may be directly tested or else all or some of the nucleic acid or protein material present in the biological sample may be isolated prior to testing. In yet another example, the sample may be partially purified or otherwise enriched prior to analysis. For example, to the extent that a biological sample comprises a very diverse cell population, it may be desirable to enrich for a sub-population of particular interest. It is within the scope of the present invention for the target cell population or molecules derived therefrom to be treated prior to testing, for example, inactivation of live virus or being run on a gel. It should also be understood that the biological sample may be freshly harvested or it may have been stored (for example by freezing) prior to testing or otherwise treated prior to testing (such as by undergoing culturing).

The choice of what type of sample is most suitable for testing in accordance with the method disclosed herein will be dependent on the nature of the situation. Preferably, said sample is a faecal (stool) sample, enema wash, surgical resection, tissue biopsy or blood sample.

In a related aspect, it has been determined that certain of the markers hereinbefore defined are more indicative of adenoma development versus cancer development or vice versa. This is an extremely valuable finding since it enables one to more specifically characterise the likely nature of a neoplasm which is detected by virtue of the method of the present invention.

Accordingly, in a related aspect the present invention is directed to a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 201328_at 205825_at 219956_at 201468_s_at 205927_s_at 221922_at 201656_at 206239_s_at 223447_at 201925_s_at 207158_at 223970_at 201926_s_at 210445_at 225835_at 202718_at 210519_s_at 226360_at 202831_at 211429_s_at 228303_at 202833_s_at 212063_at 228653_at 203124_s_at 213975_s_at 228915_at 203313_s_at 214235_at 231832_at 203860_at 214651_s_at 231941_s_at 203895_at 217523_at 232176_at 203896_s_at 217867_x_at 232481_s_at 204401_at 218086_at 234331_s_at 204885_s_at 218211_s_at 235210_s_at 205174_s_at 218796_at 235976_at 205366_s_at 219630_at 236894_at 205470_s_at 219682_s_at 238017_at 205513_at 219727_at 238984_at 205765_at 219955_at; 241031_at; and/or (ii) APOBEC1 HOXB6 QPCT BACE2 IGFBP2 RDHE2 C20orf42 ITGA6 REG4 CD44 KCNN4 RETNLB CD55 KLK11 RP5-875H10.1 CTSE L1TD1 RPESP CYP3A5 LILRB1 SERPINA1 CYP3A5P2 MLPH SLC11A2 DACH1 MSLN SLC12A2 DUOX2 MUC20 SLITRK6 ETS2 NLF1 SPINK1 FABP6 NPDC1 TBX3 FAM84A NQO1 TCN1 GALNT6 PCCA TGIF1 GPSM2 PCSK1 WDR51B GPX2 PDZK1IP1 ZNRF3 HOXA9 PLCB4 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to control levels is indicative of an adenoma cell or a cell predisposed to the onset of an adenoma state.

In another preferred embodiment of this aspect of the present invention there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 200660_at 205476_at 217430_x_at 200665_s_at 205479_s_at 217996_at 200832_s_at 205713_s_at 218507_at 200903_s_at 205815_at 218963_s_at 201014_s_at 205828_at 218984_at 201112_s_at 205886_at 219787_s_at 201195_s_at 205890_s_at 219911_s_at 201261_x_at 205910_s_at 221729_at 201292_at 205941_s_at 221730_at 201338_x_at 206224_at 221731_x_at 201479_at 206976_s_at 221923_s_at 201577_at 207173_x_at 37892_at 201601_x_at 207457_s_at 222449_at 201666_at 208079_s_at 222450_at 202310_s_at 208712_at 222549_at 202311_s_at 209218_at 222608_s_at 202403_s_at 209309_at 223062_s_at 202404_s_at 209752_at 224428_s_at 202431_s_at 209773_s_at 224646_x_at 202504_at 209774_x_at 224915_x_at 202779_s_at 209792_s_at 225295_at 202859_x_at 209875_s_at 225520_at 202954_at 209955_s_at 225664_at 202998_s_at 210052_s_at 225681_at 203083_at 210511_s_at 225767_at 203213_at 210559_s_at 225799_at 203878_s_at 210766_s_at 225806_at 204051_s_at 211506_s_at 226227_x_at 204127_at 212281_s_at 226237_at 204170_s_at 212344_at 226311_at 204320_at 212353_at 226777_at 204470_at 212354_at 226835_s_at 204475_at 213905_x_at 227140_at 204580_at 214022_s_at 229802_at 204620_s_at 214974_x_at 231766_s_at 204702_s_at 215091_s_at; 232151_at; and/or 205361_s_at (ii) AHCY DKC1 PSAT1 ANLN ECT2 PUS7 AURKA FAP REG1A AZGP1 GTF3A REG1B BGN H19 REG3A C14orf94 HIG2 RFC3 C20orf199 HSPH1 RRM2 CCL20 IFITM1 S100A11 CCND1 IL8 SCD CDC2 INHBA SFRP4 CDCA7 KLK10 SLC39A10 CDH11 KRT23 SLC7A5 CEL LOC541471 SLCO4A1 CKS2 LOXL2 SPARC CLDN1 LY6G6D SPP1 COL10A1 MMP1 SQLE COL11A1 MMP11 SULF1 COL12A1 MMP12 THBS2 COL1A1 MMP3 TIMP1 COL1A2 MTHFD1L TMEM97 COL5A2 MYC TMEPAI COL8A1 NFE2L3 TOP2A COMP NME1 TPX2 CSE1L NPM1 TRIM29 CST1 PAICS UBD CTHRC1 PFDN4 UBE2C CXCL1 PHLDA1 UBE2S CXCL2 PLAU VCAN CXCL5 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to control levels is indicative of a cancer cell or a cell predisposed to the onset of a cancerous state.

According to these aspects, said control levels are preferably non-neoplastic levels and said large intestine tissue is colorectal tissue. Even more preferably, said biological sample is a stool sample or blood sample.

In a related aspect, it has been determined that a subpopulation of the markers of the present invention are not only expressed at levels higher than normal levels, their expression pattern is uniquely characterised by the fact that expression levels above that of background control levels are not detectable in non-neoplastic tissue. This determination has therefore enabled the development of qualitative screening systems which are simply designed to detect marker expression relative to a control background level. In accordance with this aspect of the present invention, said “control level” is therefore the “background level”. Preferably, said background level is of the chosen testing methodology.

According to this aspect, there is therefore provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 202286_s_at 235976_at 209309_at 204259_at 236894_at 211506_s_at 204885_s_at 214974_x_at 205174_s_at 238984_at 219787_s_at 205825_at 241031_at 37892_at 207850_at 202311_s_at 222608_s_at 213880_at 204320_at 223062_s_at 217523_at 204475_at 225806_at 227174_at 204702_s_at 226237_at 228915_at 205910_s_at 227140_at 232252_at 206224_at 229802_at; and/or (ii) MMP1 PCSK1 ANLN MMP7 CST1 DACH1 LGR5 QPCT COL11A1 WDR72 ECT2 C14orf94 COL11A1 SLITRK6 AZGP1 COL1A1 L1TD1 REG4 DUSP27 KIAA1199 NFE2L3 NLF1 PSAT1 CEL IL8 CXCL5 CD44 TACSTD2 CXCL3 COL8A1 MSLN in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to background levels is indicative of a neoplastic cell or a cell predisposed to the onset of a neoplastic state.

In a most preferred embodiment, said genes or transcripts are selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 227140_at 227174_at 241031_at 204475_at 37892_at 211506_s_at 204259_at 202311_s_at 202286_s_at 213880_at 232252_at 226237_at; and/or (ii) MMP1 COL11A1 IL8 MMP7 COL1A1 TACSTD2 LGR5 DUSP27 COL8A1 WDR72 NLF1

Preferably, said neoplasm is an adenoma or an adenocarcinoma and said gastrointestinal tissue is colorectal tissue.

In yet another embodiment, it has been determined that a further subpopulation of these markers are more characteristic of adenoma development, while others are more characteristic of cancer development. Accordingly, there is provided a convenient means of qualitatively obtaining indicative information in relation to the characteristics of the subject neoplasm.

According to this embodiment there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 204885_s_at 217523_at 236894_at 205174_s_at 228915_at 238984_at 205825_at 235976_at 241031_at; and/or (ii) CD44 MSLN QPCT DACH1 NLF1 REG4 L1TD1 PCSK1 SLITRK6 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to background levels is indicative of an adenoma cell or a cell predisposed to the onset of an adenoma state.

In yet still another preferred embodiment there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene or genes detected by Affymetrix probeset IDs: (i) 202311_s_at 209309_at 223062_s_at 204320_at 211506_s_at 225806_at 204475_at 214974_x_at 226237_at 204702_s_at 219787_s_at 227140_at 205910_s_at 37892_at 229802_at; and/or 206224_at 222608_s_at (ii) ANLN COL1A1 IL8 AZGP1 COL8A1 MMP1 C14orf94 CST1 NFE2L3 CEL CXCL5 PSAT1 COL11A1 ECT2 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to background levels is indicative of a cancer cell or a cell predisposed to the onset of a cancerous state.

Preferably, said large intestine tissue is colorectal tissue.

More preferably, said biological sample is a blood sample or stool sample.

As detailed hereinbefore, the present invention is designed to screen for a neoplastic cell or cellular population, which is located in the large intestine. Accordingly, reference to “cell or cellular population” should be understood as a reference to an individual cell or a group of cells. Said group of cells may be a diffuse population of cells, a cell suspension, an encapsulated population of cells or a population of cells which take the form of tissue.

Reference to “expression” should be understood as a reference to the transcription and/or translation of a nucleic acid molecule. In this regard, the present invention is exemplified with respect to screening for neoplastic marker expression products taking the form of RNA transcripts (eg primary RNA or mRNA). Reference to “RNA” should be understood to encompass reference to any form of RNA, such as primary RNA or mRNA. Without limiting the present invention in any way, the modulation of gene transcription leading to increased or decreased RNA synthesis will also correlate with the translation of some of these RNA transcripts (such as mRNA) to produce a protein product. Accordingly, the present invention also extends to detection methodology which is directed to screening for modulated levels or patterns of the neoplastic marker protein products as an indicator of the neoplastic state of a cell or cellular population. Although one method is to screen for mRNA transcripts and/or the corresponding protein product, it should be understood that the present invention is not limited in this regard and extends to screening for any other form of neoplastic marker expression product such as, for example, a primary RNA transcript. It is well within the skill of the person of skill in the art to determine the most appropriate screening target for any given situation. To this end, the genes which are known to encode an expression product which is either secreted by the cell or membrane bound is detailed in the table, below. It would be appreciated that screening for neoplastic markers which are secreted or membrane bound may provide particular advantages in terms of the design of a diagnostic screening product.

The gene or genes detected by Affymetrix probe Nos: 200600_at 203961_at 212077_at 224724_at 200832_s_at 203962_s_at 212281_s_at 224915_x_at 200903_s_at 204006_s_at 212344_at 225295_at 200974_at 204122_at 212353_at 225520_at 201058_s_at 204127_at 212354_at 225541_at 201069_at 204170_s_at 212942_s_at 225664_at 201105_at 204320_at 213125_at 225710_at 201112_s_at 204351_at 213524_s_at 225767_at 201195_s_at 204401_at 213869_x_at 225799_at 201328_at 204404_at 213880_at 225806_at 201341_at 204702_s_at 214022_s_at 225835_at 201416_at 204885_s_at 214235_at 226227_x_at 201417_at 205361_s_at 214651_s_at 226311_at 201426_s_at 205366_s_at 215049_x_at 226360_at 201468_s_at 205547_s_at 217523_at 226694_at 201479_at 205765_at 217762_s_at 226777_at 201563_at 205825_at 217763_s_at 226835_s_at 201601_x_at 205890_s_at 217764_s_at 227099_s_at 201616_s_at 205927_s_at 217867_x_at 227140_at 201656_at 205941_s_at 217996_at 227174_at 201667_at 205983_at 218086_at 227475_at 201925_s_at 206286_s_at 218211_s_at 227566_at 201926_s_at 206976_s_at 218559_s_at 228303_at 202237_at 207158_at 218704_at 228653_at 202238_s_at 207173_x_at 218796_at 228754_at 202286_s_at 207191_s_at 218872_at 228915_at 202431_s_at 208079_s_at 218963_s_at 229215_at 202450_s_at 208712_at 218984_at 229802_at 202504_at 208782_at 219630_at 231766_s_at 202620_s_at 208788_at 219682_s_at 231832_at 202779_s_at 208850_s_at 219727_at 231879_at 202831_at 208851_s_at 219787_s_at 232151_at 202878_s_at 209156_s_at 219911_s_at 232176_at 202917_s_at 209218_at 219955_at 232252_at 202935_s_at 209369_at 219956_at 232481_s_at 202936_s_at 209596_at 221011_s_at 233555_s_at 202954_at 209773_s_at 221922_at 234331_s_at 203124_s_at 209955_s_at 221923_s_at 234994_at 203213_at 210052_s_at 222449_at 235210_s_at 203256_at 210445_at 222450_at 235976_at 203313_s_at 210519_s_at 222549_at 236894_at 203382_s_at 210559_s_at 222608_s_at 238017_at 203645_s_at 210766_s_at 223062_s_at 203860_at 211964_at 223235_s_at 241031_at 203878_s_at 211966_at 224428_s_at 37892_at 203895_at 212063_at 224646_x_at 60474_at 203896_s_at 212070_at 224694_at ACTA2 DUOX2 LOC541471 S100A11 AHCY DUSP27 MAFB S100A8 ANLN ECT2 MLPH S100P ANTXR1 ELOVL5 MMP11 SCD ANXA3 ENC1 MMP2 SLC11A2 APOBEC1 ETS2 MSLN SLC12A2 APOE FABP6 MSN SLC39A10 ASCL2 FAM84A MTHFD1L SLC6A6 AURKA FAP MXRA5 SLC7A5 BACE2 FCGR3B MYC SLCO4A1 C14orf94 FLJ37644 MYL9 SLITRK6 C20orf199 FOXQ1 NEBL SMOC2 C20orf42 FSTL1 NFE2L3 SORD CALD1 G0S2 NLF1 SOX4 CCND1 GALNT6 NNMT SOX9 CD163 GJA1 NPDC1 SQLE CD44 GPR56 NPM1 SULF1 CD55 GPSM2 NQO1 SULF2 CD93 GPX2 OLFML2B TACSTD2 CDC2 H19 PALM2- TAGLN CDCA7 AKAP2 TBX3 CDH11 HNT PCCA TDGF1 CDH3 HOXA9 PCSK1 TESC CKS2 HOXB6 PDZK1IP1 TGIF1 CLDN1 HSPH1 PFDN4 THY1 COL10A1 IFITM1 PHLDA1 TMEM97 COL11A1 ISLR PLCB4 TMEPAI COL12A1 ITGA6 PLOD2 TPX2 COL4A2 KCNN4 PSAT1 TRIM29 COL6A2 KIAA1199 PUS7 TYROBP CSE1L KIAA1913 RAB31 UBD CTSE KRT23 RDHE2 UBE2C CTSK L1TD1 RFC3 UBE2S CYP3A5 LBH RNF43 VIM CYP3A5P2 LGALS1 RP5-875H10.1 WDR51B DACH1 LGR5 RPESP WDR72 DKC1 LOC387763 RPL22L1 ZNRF3 DPEP1 RRM2

Reference to “nucleic acid molecule” should be understood as a reference to both deoxyribonucleic acid molecules and ribonucleic acid molecules and fragments thereof. The present invention therefore extends to both directly screening for mRNA levels in a biological sample or screening for the complementary cDNA which has been reverse-transcribed from an mRNA population of interest. It is well within the skill of the person of skill in the art to design methodology directed to screening for either DNA or RNA. As detailed above, the method of the present invention also extends to screening for the protein product translated from the subject mRNA.

Preferably, the level of gene expression is measured by reference to genes which encode a protein product and, more particularly, said level of expression is measured at the protein level. Accordingly, to the extent that the present invention is directed to screening for markers which are detailed in the preceding table, said screening is preferably directed to the encoded protein.

As detailed hereinbefore, it should be understood that although the present invention is exemplified with respect to the detection of expressed nucleic acid molecules (e.g. mRNA), it also encompasses methods of detection based on screening for the protein product of the subject genes. The present invention should also be understood to encompass methods of detection based on identifying both proteins and/or nucleic acid molecules in one or more biological samples. This may be of particular significance to the extent that some of the neoplastic markers of interest may correspond to genes or gene fragments which do not encode a protein product. Accordingly, to the extent that this occurs it would not be possible to test for a protein and the subject marker would have to be assessed on the basis of transcription expression profiles.

In terms of screening for the upregulation of expression of a marker it would also be well known to the person of skill in the art that changes which are detectable at the DNA level are indicative of changes to gene expression activity and therefore changes to expression product levels. Such changes include but are not limited to, changes to DNA methylation. Accordingly, reference herein to “screening the level of expression” and comparison of these “levels of expression” to control “levels of expression” should be understood as a reference to assessing DNA factors which are related to transcription, such as gene/DNA methylation patterns.

The term “protein” should be understood to encompass peptides, polypeptides and proteins (including protein fragments). The protein may be glycosylated or unglycosylated and/or may contain a range of other molecules fused, linked, bound or otherwise associated to the protein such as amino acids, lipids, carbohydrates or other peptides, polypeptides or proteins. Reference herein to a “protein” includes a protein comprising a sequence of amino acids as well as a protein associated with other molecules such as amino acids, lipids, carbohydrates or other peptides, polypeptides or proteins.

The proteins encoded by the neoplastic markers of the present invention may be in multimeric form meaning that two or more molecules are associated together. Where the same protein molecules are associated together, the complex is a homomultimer. An example of a homomultimer is a homodimer. Where at least one marker protein is associated with at least one non-marker protein, then the complex is a heteromultimer such as a heterodimer.

Reference to a “fragment” should be understood as a reference to a portion of the subject nucleic acid molecule or protein. This is particularly relevant with respect to screening for modulated RNA levels in stool samples since the subject RNA is likely to have been degraded or otherwise fragmented due to the environment of the gut. One may therefore actually be detecting fragments of the subject RNA molecule, which fragments are identified by virtue of the use of a suitably specific probe.

Reference to the “onset” of a neoplasm, such as adenoma or adenocarcinoma, should be understood as a reference to one or more cells of that individual exhibiting dysplasia. In this regard, the adenoma or adenocarcinoma may be well developed in that a mass of dysplastic cells has developed. Alternatively, the adenoma or adenocarcinoma may be at a very early stage in that only relatively few abnormal cell divisions have occurred at the time of diagnosis. The present invention also extends to the assessment of an individual's predisposition to the development of a neoplasm, such as an adenoma or adenocarcinoma. Without limiting the present invention in any way, changed levels of the neoplastic markers may be indicative of that individual's predisposition to developing a neoplasia, such as the future development of an adenoma or adenocarcinoma or another adenoma or adenocarcinoma.

In yet another related aspect of the present invention, markers have been identified which enable the characterisation of neoplastic tissue of the large intestine in terms of whether it is an adenoma or a cancer. This development now provides a simple yet accurate means of characterising tissue using means other than the traditional methods which are currently utilised.

According to this aspect of the present invention, there is provided a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 200884_at 214234_s_at 226248_s_at 203240_at 214235_at 226302_at 203963_at 214433_s_at 227676_at 204508_s_at 215125_s_at 227719_at 204607_at 215867_x_at 227725_at 204811_s_at 217109_at 228232_s_at 204895_x_at 217110_s_at 229070_at 204897_at 218211_s_at 231832_at 205259_at 219543_at 232176_at 205765_at 219955_at 232481_s_at 205927_s_at 221841_s_at 235976_at 208063_s_at 221874_at 236894_at 208937_s_at 223969_s_at 237521_x_at 210107_at 223970_at 242601_at 213106_at; and/or (ii) CLCA1 CTSE ATP8B1 FCGBP C6orf105 CACNA2D2 HMGCS2 CKB KLF4 RETNLB ATP8A1 CYP3A5P2 L1TD1 MUC4 CAPN9 SLITRK6 UGT1A1 NR3C2 VSIG2 SELENBP1 PBLD LOC253012 PTGER4 CA12 ST6GALNAC1 MLPH WDR51B ID1 KIAA1324 FAM3D CYP3A5 in said cell or cellular population wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to a gastrointestinal cancer cell level is indicative of an adenoma cell or a cell predisposed to the onset of an adenoma state.

In another aspect there is provided a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 200600_at 204006_s_at 213428_s_at 200665_s_at 204051_s_at 213524_s_at 200832_s_at 204122_at 213869_x_at 200974_at 204320_at 213905_x_at 200986_at 204475_at 214247_s_at 201058_s_ at 204620_s_at 215049_x_at 201069_at 205479_s_at 215076_s_at 201105_at 205547_s_at 215646_s_at 201141_at 205828_at 216442_x_at 201147_s_at 207173_x_at 217430_x_at 201150_s_at 207191_s_at 217762_s_at 201162_at 208747_s_at 217763_s_at 201163_s_at 208782_at 217764_s_at 201185_at 208788_at 218468_s_at 201261_x_at 208850_s_at 218469_at 201289_at 208851_s_at 218559_s_at 201426_s_at 209101_at 218638_s_at 201438_at 209156_s_at 219087_at 201616_s_at 209218_at 221011_s_at 201645_at 209395_at 221729_at 201667_at 209396_s_at 221730_at 201744_s_at 209596_at 221731_x_at 201792_at 209875_s_at 37892_at 201842_s_at 209955_s_at 223122_s_at 201852_x_at 210095_s_at 223235_s_at 201859_at 210495_x_at 224560_at 201893_x_at 210511_s_at 224694_at 202237_at 210764_s_at 224724_at 202238_s_at 210809_s_at 225664_at 202283_at 211161_s_at 225681_at 202291_s_at 211571_s_at 225710_at 202310_s_at 211719_x_at 225799_at 202311_s_at 211813_x_at 226237_at 202403_s_at 211896_s_at 226311_at 202404_s_at 211959_at 226694_at 202450_s_at 211964_at 226777_at 202620_s_at 211966_at 226930_at 202766_s_at 211980_at 227099_s_at 202859_x_at 211981_at 227140_at 202878_s_at 212077_at 227566_at 202917_s_at 212344_at 229218_at 202998_s_at 212353_at 229802_at 203083_at 212354_at 231579_s_at 203325_s_at 212464_s_at 231766_s_at 203382_s_at 212488_at 231879_at 203477_at 212489_at 232458_at 203570_at 212667_at 233555_s_at 203645_s_at 213125_at 234994_at 203878_s_at; and/or (ii) COL1A2 LGALS1 SRGN CTHRC1 ELOVL5 LBH FN1 MGP CTGF POSTN MMP2 TNC SPP1 LOXL2 G0S2 MMP1 MYL9 SQLE SPARC DCN EFEMP1 LUM CALD1 APOE GREM1 FBN1 MSN IL8 MMP3 IGFBP3 IGFBP5 IGFBP7 SERPINF1 SFRP2 FSTL1 ISLR SULF1 COL4A2 HNT ASPN VCAN COL5A1 COL6A3 SMOC2 OLFML2B COL8A1 HTRA1 KIAA1913 COL12A1 CYR61 PALM2-AKAP2 COL5A2 FAP SERPING1 CDH11 VIM TYROBP THBS2 TIMP2 ACTA2 COL15A1 SCD COL3A1 COL11A1 TIMP3 PLOD2 S100A8 AEBP1 MMP11 FNDC1 GJA1 CD163 SFRP4 NNMT FCGR3B INHBA COL1A1 PLAU COL6A2 SULF2 MAFB ANTXR1 COL6A1 LOC541471 GPNMB SPON2 LOC387763 BGN CTSK CHI3L1 TAGLN MXRA5 THY1 COL4A1 C1S LOXL1 RAB31 DKK3 CD93 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to a gastrointestinal adenoma cell level is indicative of a cancer or a cell predisposed to the onset of a cancerous state.

Preferably, said gastrointestinal tissue is colorectal tissue.

Reference to an “adenoma control level” or “cancer control level” should be understood as a reference to the level of said gene expression in a population of adenoma or cancer gastrointestinal cells, respectively. As discussed hereinbefore in relation to “normal levels”, the subject level may be a discrete level or a range of levels. Accordingly, the definition of “adenoma control level” or “cancer control level” should be understood to have a corresponding definition to “normal level”, albeit in the context of the expression of genes by a neoplastic population of large intestine cells.

In terms of this aspect of the present invention, the subject analysis is performed on a population of neoplastic cells. These cells may be derived in any manner, such as sloughed of neoplastic cells which have been collected via an enema wash or from a gastrointestinal sample, such as a stool sample. Alternatively, the subject cells may have been obtained via a biopsy or other surgical technique.

Without limiting this aspect of the invention in any way, several of the markers of this aspect of the present invention have been determined to be expressed at particularly significant levels above those of neoplastic cells. For example, increased expression levels of 3- and 5-fold have been observed in respect of the following markers, when assessed by the method exemplified herein, which are indicative of gastrointestinal adenomas.

Gene or genes detected by Fold Increase Affymetrix Probe No: Gene 5 210107_at CLCA1 3 203240_at FCGBP 204607_at HMGCS2 223969_s_at RETNLB 219955_at L1TD1 232481_s_at SLITRK6 228232_s_at VSIG2 242601_at LOC253012 227725_at ST6GALNAC1

In another example, increased expression levels of between 3- and 9-fold have been observed in respect of the following markers which are indicative of gastrointestinal cancers, when assessed by the method herein exemplified:

Gene or genes detected by Fold Increase Affymetrix Probe No: Gene 9 202404_s_at COL1A2 8 225681_at CTHRC1 7 212464_s_at FN1 210809_s_at POSTN 6 209875_s_at SPP1 5 227140_st MMP1 204475_at 4 200665_s_at SPARC 201744_s_at LUM 218468_s_at GREM1 202859_x_at IL8 211959_at IGFBP5 3 223122_s_at SFRP2 212353_at SULF1 219087_at ASPN 201438_at COL6A3 226237_at COL8A1 225664_at COL12A1 221730_at COL5A2 207173_x_at CDH11 203083_at THBS2 203477_at COL15A1 37892_at COL11A1 202917_s_at S100A8 226930_at FNDC1 204051_s_at SFRP4 210511_s_at INHBA 209156_s_at COL6A2 224694_at ANTXR1 201141_at GPNMB 213905_x_at BGN 205547_s_at TAGLN

According to this embodiment, there is therefore provided a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

-   -   (i) the gene or genes detected by Affymetrix probeset IDs:         -   210107_at; and/or     -   (ii) CLCA1         in a biological sample from said individual wherein a higher         level of expression of the genes or transcripts of group (i)         and/or group (ii) relative to a gastrointestinal cancer control         level is indicative of an adenoma cell or a cell predisposed to         the onset of an adenoma state.

In another embodiment, there is provided a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 203240_at 219955_at 242601_at 204607_at 232481_s_at 227725_at 223969_s_at 228232_s_at; and/or (ii) FCGBP L1TD1 LOC253012 HMGCS2 SLITRK6 ST6GALNAC1 RETNLB VSIG2 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to a gastrointestinal cancer control level is indicative of an adenoma cell or a cell predisposed to the onset of an adenoma state.

Preferably, said gastrointestinal tissue is colorectal tissue.

Still more preferably, said biological sample is a tissue sample.

In another preferred embodiment the present invention is directed to a method of characterising a cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 202404_s_at 210809_s_at 227140_at 225681_at 209875_s_at 204475_at 212464_s_at; and/or (ii) COL1A2 FN1 SPP1 CTHRC1 POSTN MMP1 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or (ii) relative to a gastrointestinal adenoma control level is indicative of a cancer or a cell predisposed to the onset of a cancerous state.

In yet another preferred embodiment the present invention is directed to a method of characterising a cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 200665_s_at 218468_s_at 211959_at 201744_s_at 202859_x_at; and/or (ii) SPARC GREM1 IGFBP5 LUM IL8 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or (ii) relative to a gastrointestinal adenoma control level is indicative of a cancer or a cell predisposed to the onset of a cancerous state.

In still yet another preferred embodiment the present invention is directed to a method of characterising a cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 223122_s_at 207173_x_at 210511_s_at 212353_at 203083_at 209156_s_at 219087_at 203477_at 224694_at 201438_at 37892_at 201141_at 226237_at 202917_s_at 213905_x_at 225664_at 226930_at 205547_s_at 221730_at 204051_s_at; and/or (ii) SFRP2 CDH11 INHBA SULF1 THBS2 COL6A2 ASPN COL15A1 ANTXR1 COL6A3 COL11A1 GPNMB COL8A1 S100A8 BGN COL12A1 FNDC1 TAGLN COL5A2 SFRP4 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or (ii) relative to a gastrointestinal adenoma control level is indicative of a cancer or a cell predisposed to the onset of a cancerous state.

Preferably, said gastrointestinal tissue is colorectal tissue.

Even more preferably, said biological sample is a tissue sample.

In still another related aspect it has been determined that a subset of the markers of this aspect of the present invention are useful as qualitative markers of neoplastic tissue characterisation in that these markers, if detectable above background levels in neoplastic tissue are indicative of either adenoma or cancerous tissue.

According to this aspect, the present invention provides a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 235976_at 236894_at; and/or (ii) SLITRK6 L1TD1 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or (ii) relative to neoplastic tissue background levels is indicative of an adenoma cell or a cell predisposed to the onset of an adenoma state.

In another aspect the present invention provides a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: (i) 202311_s_at 209396_s_at 226237_at 204320_at 215646_s_at 227140_at 204475_at 37892_at 229802_at 209395_at; and/or (ii) COL1A1 VCAN CHI3L1 MMP1 COL8A1 COL11A1 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or (ii) relative to neoplastic tissue background neoplastic cell levels is indicative of a cancer or a cell predisposed to the onset of a cancerous state.

Preferably, said gastrointestinal tissue is colorectal tissue.

Still more preferably, said biological sample is a tissue sample.

In a most preferred embodiment, the methods of the present invention are preferably directed to screening for proteins encoded by the markers of the present invention.

Although the preferred method is to detect the expression products of the neoplastic markers for the purpose of diagnosing neoplasia development or predisposition thereto, the detection of converse changes in the levels of said markers may be desired under certain circumstances, for example, to monitor the effectiveness of therapeutic or prophylactic treatment directed to modulating a neoplastic condition, such as adenoma or adenocarcinoma development. For example, where elevated levels of the subject markers indicate that an individual has developed a condition characterised by adenoma or adenocarcinoma development, for example, screening for a decrease in the levels of these markers subsequently to the onset of a therapeutic regime may be utilised to indicate reversal or other form of improvement of the subject individual's condition.

The method of the present invention is therefore useful as a one-time test or as an on-going monitor of those individuals thought to be at risk of neoplasia development or as a monitor of the effectiveness of therapeutic or prophylactic treatment regimes directed to inhibiting or otherwise slowing neoplasia development. In these situations, mapping the modulation of neoplastic marker expression levels in any one or more classes of biological samples is a valuable indicator of the status of an individual or the effectiveness of a therapeutic or prophylactic regime which is currently in use. Accordingly, the method of the present invention should be understood to extend to monitoring for increases or decreases in marker expression levels in an individual relative to their normal level (as hereinbefore defined), background control levels, cancer levels, adenoma levels or relative to one or more earlier marker expression levels determined from a biological sample of said individual.

Means of testing for the subject expressed neoplasm markers in a biological sample can be achieved by any suitable method, which would be well known to the person of skill in the art, such as but not limited to:

-   (i) In vivo detection.     -   Molecular Imaging may be used following administration of         imaging probes or reagents capable of disclosing altered         expression of the markers in the intestinal tissues.     -   Molecular imaging (Moore et al., BBA, 1402:239-249, 1988;         Weissleder et al., Nature Medicine 6:351-355, 2000) is the in         vivo imaging of molecular expression that correlates with the         macro-features currently visualized using “classical” diagnostic         imaging techniques such as X-Ray, computed tomography (CT), MRI,         Positron Emission Tomography (PET) or endoscopy. -   (ii) Detection of up-regulation of RNA expression in the cells by     Fluorescent In Situ

Hybridization (FISH), or in extracts from the cells by technologies such as Quantitative Reverse Transcriptase Polymerase Chain Reaction (QRTPCR) or Flow cytometric qualification of competitive RT-PCR products (Wedemeyer et al., Clinical Chemistry 48:9 1398-1405, 2002).

-   (iii) Assessment of expression profiles of RNA, for example by array     technologies (Alon et al., Proc. Natl. Acad. Sci. USA: 96,     6745-6750, June 1999).

A “microarray” is a linear or multi-dimensional array of preferably discrete regions, each having a defined area, formed on the surface of a solid support. The density of the discrete regions on a microarray is determined by the total numbers of target polynucleotides to be detected on the surface of a single solid phase support. As used herein, a DNA microarray is an array of oligonucleotide probes placed onto a chip or other surfaces used to detect complementary oligonucleotides from a complex nucleic acid mixture. Since the position of each particular group of probes in the array is known, the identities of the target polynucleotides can be determined based on their binding to a particular position in the microarray.

Recent developments in DNA microarray technology make it possible to conduct a large scale assay of a plurality of target nucleic acid molecules on a single solid phase support. U.S. Pat. No. 5,837,832 (Chee et al.) and related patent applications describe immobilizing an array of oligonucleotide probes for hybridization and detection of specific nucleic acid sequences in a sample. Target polynucleotides of interest isolated from a tissue of interest are hybridized to the DNA chip and the specific sequences detected based on the target polynucleotides' preference and degree of hybridization at discrete probe locations. One important use of arrays is in the analysis of differential gene expression, where the profile of expression of genes in different cells or tissues, often a tissue of interest and a control tissue, is compared and any differences in gene expression among the respective tissues are identified. Such information is useful for the identification of the types of genes expressed in a particular tissue type and diagnosis of conditions based on the expression profile.

In one example, RNA from the sample of interest is subjected to reverse transcription to obtain labelled cDNA. See U.S. Pat. No. 6,410,229 (Lockhart et al.) The cDNA is then hybridized to oligonucleotides or cDNAs of known sequence arrayed on a chip or other surface in a known order. In another example, the RNA is isolated from a biological sample and hybridised to a chip on which are anchored cDNA probes. The location of the oligonucleotide to which the labelled cDNA hybridizes provides sequence information on the cDNA, while the amount of labelled hybridized RNA or cDNA provides an estimate of the relative representation of the RNA or cDNA of interest. See Schena, et al. Science 270:467-470 (1995). For example, use of a cDNA microarray to analyze gene expression patterns in human cancer is described by DeRisi, et al. (Nature Genetics 14:457-460 (1996)).

In a preferred embodiment, nucleic acid probes corresponding to the subject nucleic acids are made. The nucleic acid probes attached to the microarray are designed to be substantially complementary to the nucleic acids of the biological sample such that specific hybridization of the target sequence and the probes of the present invention occurs. This complementarity need not be perfect, in that there may be any number of base pair mismatches that will interfere with hybridization between the target sequence and the single stranded nucleic acids of the present invention. It is expected that the overall homology of the genes at the nucleotide level probably will be about 40% or greater, probably about 60% or greater, and even more probably about 80% or greater; and in addition that there will be corresponding contiguous sequences of about 8-12 nucleotides or longer. However, if the number of mutations is so great that no hybridization can occur under even the least stringent of hybridization conditions, the sequence is not a complementary target sequence. Thus, by “substantially complementary” herein is meant that the probes are sufficiently complementary to the target sequences to hybridize under normal reaction conditions, particularly high stringency conditions.

A nucleic acid probe is generally single stranded but can be partly single and partly double stranded. The strandedness of the probe is dictated by the structure, composition, and properties of the target sequence. In general, the oligonucleotide probes range from about 6, 8, 10, 12, 15, 20, 30 to about 100 bases long, with from about 10 to about 80 bases being preferred, and from about 15 to about 40 bases being particularly preferred. That is, generally entire genes are rarely used as probes. In some embodiments, much longer nucleic acids can be used, up to hundreds of bases. The probes are sufficiently specific to hybridize to a complementary template sequence under conditions known by those of skill in the art. The number of mismatches between the probe's sequences and their complementary template (target) sequences to which they hybridize during hybridization generally do not exceed 15%, usually do not exceed 10% and preferably do not exceed 5%, as-determined by BLAST (default settings).

Oligonucleotide probes can include the naturally-occurring heterocyclic bases normally found in nucleic acids (uracil, cytosine, thymine, adenine and guanine), as well as modified bases and base analogues. Any modified base or base analogue compatible with hybridization of the probe to a target sequence is useful in the practice of the invention. The sugar or glycoside portion of the probe can comprise deoxyribose, ribose, and/or modified forms of these sugars, such as, for example, 2′-O-alkyl ribose. In a preferred embodiment, the sugar moiety is 2′-deoxyribose; however, any sugar moiety that is compatible with the ability of the probe to hybridize to a target sequence can be used.

In one embodiment, the nucleoside units of the probe are linked by a phosphodiester backbone, as is well known in the art. In additional embodiments, internucleotide linkages can include any linkage known to one of skill in the art that is compatible with specific hybridization of the probe including, but not limited to phosphorothioate, methylphosphonate, sulfamate (e.g., U.S. Pat. No. 5,470,967) and polyamide (i.e., peptide nucleic acids). Peptide nucleic acids are described in Nielsen et al. (1991) Science 254: 1497-1500, U.S. Pat. No. 5,714,331, and Nielsen (1999) Curr. Opin. Biotechnol. 10:71-75.

In certain embodiments, the probe can be a chimeric molecule; i.e., can comprise more than one type of base or sugar subunit, and/or the linkages can be of more than one type within the same primer. The probe can comprise a moiety to facilitate hybridization to its target sequence, as are known in the art, for example, intercalators and/or minor groove binders. Variations of the bases, sugars, and internucleoside backbone, as well as the presence of any pendant group on the probe, will be compatible with the ability of the probe to bind, in a sequence-specific fashion, with its target sequence. A large number of structural modifications, are possible within these bounds. Advantageously, the probes according to the present invention may have structural characteristics such that they allow the signal amplification, such structural characteristics being, for example, branched DNA probes as those described by Urdea et al. (Nucleic Acids Symp. Ser., 24:197-200 (1991)) or in the European Patent No. EP-0225,807. Moreover, synthetic methods for preparing the various heterocyclic bases, sugars, nucleosides and nucleotides that form the probe, and preparation of oligonucleotides of specific predetermined sequence, are well-developed and known in the art. A preferred method for oligonucleotide synthesis incorporates the teaching of U.S. Pat. No. 5,419,966.

Multiple probes may be designed for a particular target nucleic acid to account for polymorphism and/or secondary structure in the target nucleic acid, redundancy of data and the like. In some embodiments, where more than one probe per sequence is used, either overlapping probes or probes to different sections of a single target gene are used. That is, two, three, four or more probes, are used to build in a redundancy for a particular target. The probes can be overlapping (i.e. have some sequence in common), or are specific for distinct sequences of a gene. When multiple target polynucleotides are to be detected according to the present invention, each probe or probe group corresponding to a particular target polynucleotide is situated in a discrete area of the microarray.

Probes may be in solution, such as in wells or on the surface of a micro-array, or attached to a solid support. Examples of solid support materials that can be used include a plastic, a ceramic, a metal, a resin, a gel and a membrane. Useful types of solid supports include plates, beads, magnetic material, microbeads, hybridization chips, membranes, crystals, ceramics and self-assembling monolayers. One example comprises a two-dimensional or three-dimensional matrix, such as a gel or hybridization chip with multiple probe binding sites (Pevzner et al., J. Biomol. Struc. & Dyn. 9:399-410, 1991; Maskos and Southern, Nuc. Acids Res. 20:1679-84, 1992). Hybridization chips can be used to construct very large probe arrays that are subsequently hybridized with a target nucleic acid. Analysis of the hybridization pattern of the chip can assist in the identification of the target nucleotide sequence. Patterns can be manually or computer analyzed, but it is clear that positional sequencing by hybridization lends itself to computer analysis and automation. In another example, one may use an Affymetrix chip on a solid phase structural support in combination with a fluorescent bead based approach. In yet another example, one may utilise a cDNA microarray. In this regard, the oligonucleotides described by Lockkart et al. (i.e. Affymetrix synthesis probes in situ on the solid phase) are particularly preferred, that is, photolithography.

As will be appreciated by those in the art, nucleic acids can be attached or immobilized to a solid support in a wide variety of ways. By “immobilized” herein is meant the association or binding between the nucleic acid probe and the solid support is sufficient to be stable under the conditions of binding, washing, analysis, and removal. The binding can be covalent or non-covalent. By “non-covalent binding” and grammatical equivalents herein is meant one or more of either electrostatic, hydrophilic, and hydrophobic interactions. Included in non-covalent binding is the covalent attachment of a molecule, such as streptavidin, to the support and the non-covalent binding of the biotinylated probe to the streptavidin. By “covalent binding” and grammatical equivalents herein is meant that the two moieties, the solid support and the probe, are attached by at least one bond, including sigma bonds, pi bonds and coordination bonds. Covalent bonds can be formed directly between the probe and the solid support or can be formed by a cross linker or by inclusion of a specific reactive group on either the solid support or the probe or both molecules. Immobilization may also involve a combination of covalent and non-covalent interactions.

Nucleic acid probes may be attached to the solid support by covalent binding such as by conjugation with a coupling agent or by covalent or non-covalent binding such as electrostatic interactions, hydrogen bonds or antibody-antigen coupling, or by combinations thereof. Typical coupling agents include biotin/avidin, biotin/streptavidin, Staphylococcus aureus protein A/IgG antibody F, fragment, and streptavidin/protein A chimeras (T. Sano and C. R. Cantor, Bio/Technology 9:1378-81 (1991)), or derivatives or combinations of these agents. Nucleic acids may be attached to the solid support by a photocleavable bond, an electrostatic bond, a disulfide bond, a peptide bond, a diester bond or a combination of these sorts of bonds. The array may also be attached to the solid support by a selectively releasable bond such as 4,4′-dimethoxytrityl or its derivative. Derivatives which have been found to be useful include 3 or 4 [bis-(4-methoxyphenyl)]-methyl-benzoic acid, N-succinimidyl-3 or 4 [bis-(4-methoxyphenyl)]-methyl-benzoic acid, N-succinimidyl-3 or 4 [bis-(4-methoxyphenyl)]-hydroxymethyl-benzoic acid, N-succinimidyl-3 or 4 [bis-(4-methoxyphenyl)]-chloromethyl-benzoic acid, and salts of these acids.

In general, the probes are attached to the microarray in a wide variety of ways, as will be appreciated by those in the art. As described herein, the nucleic acids can either be synthesized first, with subsequent attachment to the microarray, or can be directly synthesized on the microarray.

The microarray comprises a suitable solid substrate. By “substrate” or “solid support” or other grammatical equivalents herein is meant any material that can be modified to contain discrete individual sites appropriate for the attachment or association of the nucleic acid probes and is amenable to at least one detection method. The solid phase support of the present invention can be of any solid materials and structures suitable for supporting nucleotide hybridization and synthesis. Preferably, the solid phase support comprises at least one substantially rigid surface on which the primers can be immobilized and the reverse transcriptase reaction performed. The substrates with which the polynucleotide microarray elements are stably associated and may be fabricated from a variety of materials, including plastics, ceramics, metals, acrylamide, cellulose, nitrocellulose, glass, polystyrene, polyethylene vinyl acetate, polypropylene, polymethacrylate, polyethylene, polyethylene oxide, polysilicates, polycarbonates, Teflon, fluorocarbons, nylon, silicon rubber, polyanhydrides, polyglycolic acid, polylactic acid, polyorthoesters, polypropylfumerate, collagen, glycosaminoglycans, and polyamino acids. Substrates may be two-dimensional or three-dimensional in form, such as gels, membranes, thin films, glasses, plates, cylinders, beads, magnetic beads, optical fibers, woven fibers, etc. A preferred form of array is a three-dimensional array. A preferred three-dimensional array is a collection of tagged beads. Each tagged bead has different primers attached to it. Tags are detectable by signalling means such as color (Luminex, Illumina) and electromagnetic field (Pharmaseq) and signals on tagged beads can even be remotely detected (e.g., using optical fibers). The size of the solid support can be any of the standard microarray sizes, useful for DNA microarray technology, and the size may be tailored to fit the particular machine being used to conduct a reaction of the invention. In general, the substrates allow optical detection and do not appreciably fluoresce.

In one embodiment, the surface of the microarray and the probe may be derivatized with chemical functional groups for subsequent attachment of the two. Thus, for example, the microarray is derivatized with a chemical functional group including, but not limited to, amino groups, carboxy groups, oxo groups and thiol groups, with amino groups being particularly preferred. Using these functional groups, the probes can be attached using functional groups on the probes. For example, nucleic acids containing amino groups can be attached to surfaces comprising amino groups, for example using linkers as are known in the art; for example, homo- or hetero-bifunctional linkers as are well known. In addition, in some cases, additional linkers, such as alkyl groups (including substituted and heteroalkyl groups) may be used.

In this embodiment, the oligonucleotides are synthesized as is known in the art, and then attached to the surface of the solid support. As will be appreciated by those skilled in the art, either the 5′ or 3′ terminus may be attached to the solid support, or attachment may be via an internal nucleoside. In an additional embodiment, the immobilization to the solid support may be very strong, yet non-covalent. For example, biotinylated oligonucleotides can be made, which bind to surfaces covalently coated with streptavidin, resulting in attachment.

The arrays may be produced according to any convenient methodology, such as preforming the polynucleotide microarray elements and then stably associating them with the surface. Alternatively, the oligonucleotides may be synthesized on the surface, as is known in the art. A number of different array configurations and methods for their production are known to those of skill in the art and disclosed in WO 95/25116 and WO 95/35505 (photolithographic techniques), U.S. Pat. No. 5,445,934 (in situ synthesis by photolithography), U.S. Pat. No. 5,384,261 (in situ synthesis by mechanically directed flow paths); and U.S. Pat. No. 5,700,637 (synthesis by spotting, printing or coupling); the disclosure of which are herein incorporated in their entirety by reference. Another method for coupling DNA to beads uses specific ligands attached to the end of the DNA to link to ligand-binding molecules attached to a bead. Possible ligand-binding partner pairs include biotin-avidin/streptavidin, or various antibody/antigen pairs such as digoxygenin-antidigoxygenin antibody (Smith et al., Science 258:1122-1126 (1992)). Covalent chemical attachment of DNA to the support can be accomplished by using standard coupling agents to link the 5′-phosphate on the DNA to coated microspheres through a phosphoamidate bond. Methods for immobilization of oligonucleotides to solid-state substrates are well established. See Pease et al., Proc. Natl. Acad. Sci. USA 91(11):5022-5026 (1994). A preferred method of attaching oligonucleotides to solid-state substrates is described by Guo et al., Nucleic Acids Res. 22:5456-5465 (1994). Immobilization can be accomplished either by in situ DNA synthesis (Maskos and Southern, supra) or by covalent attachment of chemically synthesized oligonucleotides (Guo et al., supra) in combination with robotic arraying technologies.

In addition to the solid-phase technology represented by microarray arrays, gene expression can also be quantified using liquid-phase assays. One such system is kinetic polymerase chain reaction (PCR). Kinetic PCR allows for the simultaneous amplification and quantification of specific nucleic acid sequences. The specificity is derived from synthetic oligonucleotide primers designed to preferentially adhere to single-stranded nucleic acid sequences bracketing the target site. This pair of oligonucleotide primers form specific, non-covalently bound complexes on each strand of the target sequence.

These complexes facilitate in vitro transcription of double-stranded DNA in opposite orientations. Temperature cycling of the reaction mixture creates a continuous cycle of primer binding, transcription, and re-melting of the nucleic acid to individual strands. The result is an exponential increase of the target dsDNA product. This product can be quantified in real time either through the use of an intercalating dye or a sequence specific probe. SYBR(r) Green 1, is an example of an intercalating dye, that preferentially binds to dsDNA resulting in a concomitant increase in the fluorescent signal. Sequence specific probes, such as used with TaqMan technology, consist of a fluorochrome and a quenching molecule covalently bound to opposite ends of an oligonucleotide. The probe is designed to selectively bind the target DNA sequence between the two primers. When the DNA strands are synthesized during the PCR reaction, the fluorochrome is cleaved from the probe by the exonuclease activity of the polymerase resulting in signal dequenching. The probe signalling method can be more specific than the intercalating dye method, but in each case, signal strength is proportional to the dsDNA product produced. Each type of quantification method can be used in multi-well liquid phase arrays with each well representing primers and/or probes specific to nucleic acid sequences of interest. When used with messenger RNA preparations of tissues or cell lines, an array of probe/primer reactions can simultaneously quantify the expression of multiple gene products of interest. See Germer et al., Genome Res. 10:258-266 (2000); Heid et al., Genome Res. 6:986-994 (1996).

-   (iv) Measurement of altered neoplastic marker protein levels in cell     extracts, for example by immunoassay.

Testing for proteinaceous neoplastic marker expression product in a biological sample can be performed by any one of a number of suitable methods which are well known to those skilled in the art. Examples of suitable methods include, but are not limited to, antibody screening of tissue sections, biopsy specimens or bodily fluid samples.

To the extent that antibody based methods of diagnosis are used, the presence of the marker protein may be determined in a number of ways such as by Western blotting, ELISA or flow cytometry procedures. These, of course, include both single-site and two-site or “sandwich” assays of the non-competitive types, as well as in the traditional competitive binding assays. These assays also include direct binding of a labelled antibody to a target.

Sandwich assays are among the most useful and commonly used assays. A number of variations of the sandwich assay technique exist, and all are intended to be encompassed by the present invention. Briefly, in a typical forward assay, an unlabelled antibody is immobilized on a solid substrate and the sample to be tested brought into contact with the bound molecule. After a suitable period of incubation, for a period of time sufficient to allow formation of an antibody-antigen complex, a second antibody specific to the antigen, labelled with a reporter molecule capable of producing a detectable signal is then added and incubated, allowing time sufficient for the formation of another complex of antibody-antigen-labelled antibody. Any unreacted material is washed away, and the presence of the antigen is determined by observation of a signal produced by the reporter molecule. The results may either be qualitative, by simple observation of the visible signal, or may be quantitated by comparing with a control sample. Variations on the forward assay include a simultaneous assay, in which both sample and labelled antibody are added simultaneously to the bound antibody. These techniques are well known to those skilled in the art, including any minor variations as will be readily apparent.

In the typical forward sandwich assay, a first antibody having specificity for the marker or antigenic parts thereof, is either covalently or passively bound to a solid surface. The solid surface is typically glass or a polymer, the most commonly used polymers being cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene. The solid supports may be in the form of tubes, beads, discs of microplates, or any other surface suitable for conducting an immunoassay. The binding processes are well-known in the art and generally consist of cross-linking, covalently binding or physically adsorbing, the polymer-antibody complex is washed in preparation for the test sample. An aliquot of the sample to be tested is then added to the solid phase complex and incubated for a period of time sufficient (e.g. 2-40 minutes) and under suitable conditions (e.g. 25° C.) to allow binding of any subunit present in the antibody. Following the incubation period, the antibody subunit solid phase is washed and dried and incubated with a second antibody specific for a portion of the antigen. The second antibody is linked to a reporter molecule which is used to indicate the binding of the second antibody to the antigen.

An alternative method involves immobilizing the target molecules in the biological sample and then exposing the immobilized target to specific antibody which may or may not be labelled with a reporter molecule. Depending on the amount of target and the strength of the reporter molecule signal, a bound target may be detectable by direct labelling with the antibody. Alternatively, a second labelled antibody, specific to the first antibody is exposed to the target-first antibody complex to form a target-first antibody-second antibody tertiary complex. The complex is detected by the signal emitted by the reporter molecule.

By “reporter molecule” as used in the present specification, is meant a molecule which, by its chemical nature, provides an analytically identifiable signal which allows the detection of antigen-bound antibody. Detection may be either qualitative or quantitative. The most commonly used reporter molecules in this type of assay are either enzymes, fluorophores or radionuclide containing molecules (i.e. radioisotopes) and chemiluminescent molecules.

In the case of an enzyme immunoassay, an enzyme is conjugated to the second antibody, generally by means of glutaraldehyde or periodate. As will be readily recognized, however, a wide variety of different conjugation techniques exist, which are readily available to the skilled artisan. Commonly used enzymes include horseradish peroxidase, glucose oxidase, beta-galactosidase and alkaline phosphatase, amongst others. The substrates to be used with the specific enzymes are generally chosen for the production, upon hydrolysis by the corresponding enzyme, of a detectable color change. Examples of suitable enzymes include alkaline phosphatase and peroxidase. It is also possible to employ fluorogenic substrates, which yield a fluorescent product rather than the chromogenic substrates noted above. In all cases, the enzyme-labelled antibody is added to the first antibody hapten complex, allowed to bind, and then the excess reagent is washed away. A solution containing the appropriate substrate is then added to the complex of antibody-antigen-antibody. The substrate will react with the enzyme linked to the second antibody, giving a qualitative visual signal, which may be further quantitated, usually spectrophotometrically, to give an indication of the amount of antigen which was present in the sample. “Reporter molecule” also extends to use of cell agglutination or inhibition of agglutination such as red blood cells on latex beads, and the like.

Alternately, fluorescent compounds, such as fluorecein and rhodamine, may be chemically coupled to antibodies without altering their binding capacity. When activated by illumination with light of a particular wavelength, the fluorochrome-labelled antibody adsorbs the light energy, inducing a state to excitability in the molecule, followed by emission of the light at a characteristic color visually detectable with a light microscope. As in the EIA, the fluorescent labelled antibody is allowed to bind to the first antibody-hapten complex. After washing off the unbound reagent, the remaining tertiary complex is then exposed to the light of the appropriate wavelength the fluorescence observed indicates the presence of the hapten of interest. Immunofluorescence and EIA techniques are both very well established in the art and are particularly preferred for the present method. However, other reporter molecules, such as radioisotope, chemiluminescent or bioluminescent molecules, may also be employed.

-   (v) Without limiting the present invention to any one theory or mode     of action, during development gene expression is regulated by     processes that alter the availability of genes for expression in     different cell lineages without any alteration in gene sequence, and     these states can be inherited through a cell division—a process     called epigenetic inheritance. Epigenetic inheritance is determined     by a combination of DNA methylation (modification of cytosine to     give 5-methyl cytosine, 5 meC) and by modifications of the histone     chromosomal proteins that package DNA. Thus methylation of DNA at     CpG sites and modifications such as deacetylation of histone H3 on     lysine 9, and methylation on lysine 9 or 27 are associated with     inactive chromatin, while the converse state of a lack of DNA     methylation, acetylation of lysine 9 of histone H3 is associated     with open chromatin and active gene expression. In cancer, this     epigenetic regulation of gene expression is frequently found to be     disrupted (Esteller & Herman, 2000; Jones & Baylin, 2002). Genes     such as tumour suppressor or metastasis suppressor genes are often     found to be silenced by DNA methylation, while other genes may be     hypomethylated and inappropriately expressed. Thus, among genes that     elevated or inappropriate expression in cancer, this in some     instances is characterised by a loss of methylation of the promoter     or regulatory region of the gene.

A variety of methods are available for detection of aberrantly methylated DNA of a specific gene, even in the presence of a large excess of normal DNA (Clark 2007). Thus, elevated expression of certain genes may be detected through detection of the presence of hypomethylated sequences in tissue, bodily fluid or other patient samples.

Epigenetic alterations and chromatin changes in cancer are also evident in the altered association of modified histones with specific genes(Esteller, 2007); for example activated genes are often found associated with histone H3 that is acetylated on lysine 9 and methylated on lysine 4. The use of antibodies targeted to altered histones allows for the isolation of DNA associated with particular chromatin states and has potential use in cancer diagnosis.

-   (vi) Determining altered expression of protein neoplastic markers on     the cell surface, for example by immunohistochemistry. -   (vii) Determining altered protein expression based on any suitable     functional test, enzymatic test or immunological test in addition to     those detailed in points (iv) and (v) above.

A person of ordinary skill in the art could determine, as a matter of routine procedure, the appropriateness of applying a given method to a particular type of biological sample.

Without limiting the present invention in any way, and as detailed above, gene expression levels can be measured by a variety of methods known in the art. For example, gene transcription or translation products can be measured. Gene transcription products, i.e., RNA, can be measured, for example, by hybridization assays, run-off assays, Northern blots, or other methods known in the art.

Hybridization assays generally involve the use of oligonucleotide probes that hybridize to the single-stranded RNA transcription products. Thus, the oligonucleotide probes are complementary to the transcribed RNA expression product. Typically, a sequence-specific probe can be directed to hybridize to RNA or cDNA. A “nucleic acid probe”, as used herein, can be a DNA probe or an RNA probe that hybridizes to a complementary sequence. One of skill in the art would know how to design such a probe such that sequence specific hybridization will occur. One of skill in the art will further know how to quantify the amount of sequence specific hybridization as a measure of the amount of gene expression for the gene was transcribed to produce the specific RNA.

The hybridization sample is maintained under conditions that are sufficient to allow specific hybridization of the nucleic acid probe to a specific gene expression product. “Specific hybridization”, as used herein, indicates near exact hybridization (e.g., with few if any mismatches). Specific hybridization can be performed under high stringency conditions or moderate stringency conditions. In one embodiment, the hybridization conditions for specific hybridization are high stringency. For example, certain high stringency conditions can be used to distinguish perfectly complementary nucleic acids from those of less complementarity. “High stringency conditions”, “moderate stringency conditions” and “low stringency conditions” for nucleic acid hybridizations are explained on pages 2.10.1-2.10.16 and pages 6.3.1-6.3.6 in Current Protocols in Molecular Biology (Ausubel, F. et al., “Current Protocols in Molecular Biology”, John Wiley & Sons, (1998), the entire teachings of which are incorporated by reference herein). The exact conditions that determine the stringency of hybridization depend not only on ionic strength (e.g., 0.2.times.SSC, 0.1.times.SSC), temperature (e.g., room temperature, 42° C., 68° C.) and the concentration of destabilizing agents such as formamide or denaturing agents such as SDS, but also on factors such as the length of the nucleic acid sequence, base composition, percent mismatch between hybridizing sequences and the frequency of occurrence of subsets of that sequence within other non-identical sequences. Thus, equivalent conditions can be determined by varying one or more of these parameters while maintaining a similar degree of identity or similarity between the two nucleic acid molecules. Typically, conditions are used such that sequences at least about 60%, at least about 70%, at least about 80%, at least about 90% or at least about 95% or more identical to each other remain hybridized to one another. By varying hybridization conditions from a level of stringency at which no hybridization occurs to a level at which hybridization is first observed, conditions that will allow a given sequence to hybridize (e.g., selectively) with the most complementary sequences in the sample can be determined.

Exemplary conditions that describe the determination of wash conditions for moderate or low stringency conditions are described in Kraus, M. and Aaronson, S., 1991. Methods Enzymol., 200:546-556; and in, Ausubel et al., Current Protocols in Molecular Biology, John Wiley & Sons, (1998). Washing is the step in which conditions are usually set so as to determine a minimum level of complementarity of the hybrids. Generally, starting from the lowest temperature at which only homologous hybridization occurs, each ° C. by which the final wash temperature is reduced (holding SSC concentration constant) allows an increase by 1% in the maximum mismatch percentage among the sequences that hybridize. Generally, doubling the concentration of SSC results in an increase in T_(m) of about 17° C. Using these guidelines, the wash temperature can be determined empirically for high, moderate or low stringency, depending on the level of mismatch sought. For example, a low stringency wash can comprise washing in a solution containing 0.2.times.SSC/0.1% SDS for 10 minutes at room temperature; a moderate stringency wash can comprise washing in a pre-warmed solution (42° C.) solution containing 0.2.times.SSC/0.1% SDS for 15 minutes at 42° C.; and a high stringency wash can comprise washing in pre-warmed (68° C.) solution containing 0.1.times.SSC/0.1% SDS for 15 minutes at 68° C. Furthermore, washes can be performed repeatedly or sequentially to obtain a desired result as known in the art. Equivalent conditions can be determined by varying one or more of the parameters given as an example, as known in the art, while maintaining a similar degree of complementarity between the target nucleic acid molecule and the primer or probe used (e.g., the sequence to be hybridized).

A related aspect of the present invention provides a molecular array, which array comprises a plurality of:

-   (i) nucleic acid molecules comprising a nucleotide sequence     corresponding to any one or more of the neoplastic marker genes     hereinbefore described or a sequence exhibiting at least 80%     identity thereto or a functional derivative, fragment, variant or     homologue of said nucleic acid molecule; or -   (ii) nucleic acid molecules comprising a nucleotide sequence capable     of hybridising to any one or more of the sequences of (i) under     medium stringency conditions or a functional derivative, fragment,     variant or homologue of said nucleic acid molecule; or -   (iii) nucleic acid probes or oligonucleotides comprising a     nucleotide sequence capable of hybridising to any one or more of the     sequences of (i) under medium stringency conditions or a functional     derivative, fragment, variant or homologue of said nucleic acid     molecule; or -   (iv) probes capable of binding to any one or more of the proteins     encoded by the nucleic acid molecules of (i) or a derivative,     fragment or, homologue thereof     wherein the level of expression of said marker genes of (i) or     proteins of (iv) is indicative of the neoplastic state of a cell or     cellular subpopulation derived from the large intestine.

Preferably, said percent identity is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%.

Low stringency includes and encompasses from at least about 1% v/v to at least about 15% v/v formamide and from at least about 1M to at least about 2M salt for hybridisation, and at least about 1M to at least about 2M salt for washing conditions. Alternative stringency conditions may be applied where necessary, such as medium stringency, which includes and encompasses from at least about 16% v/v at least about 30% v/v formamide and from at least about 0.5M to at least about 0.9M salt for hybridisation, and at least about 0.5M to at least about 0.9M salt for washing conditions, or high stringency, which includes and encompasses from at least about 31% v/v to at least about 50% v/v formamide and from at least about 0.01M to at least about 0.15M salt for hybridisation, and at least about 0.01M to at least about 0.15M salt for washing conditions. In general, washing is carried out at T_(m)=69.3+0.41 (G+C) % [19]=−12° C. However, the T_(m) of a duplex DNA decreases by 1° C. with every increase of 1% in the number of mismatched based pairs (Bonner et al (1973) J. Mol. Biol. 81:123).

Preferably, the subject probes are designed to bind to the nucleic acid or protein to which they are directed with a level of specificity which minimises the incidence of non-specific reactivity. However, it would be appreciated that it may not be possible to eliminate all potential cross-reactivity or non-specific reactivity, this being an inherent limitation of any probe based system.

In terms of the probes which are used to detect the subject proteins, they may take any suitable form including antibodies and aptamers.

A library or array of nucleic acid or protein probes provides rich and highly valuable information. Further, two or more arrays or profiles (information obtained from use of an array) of such sequences are useful tools for comparing a test set of results with a reference, such as another sample or stored calibrator. In using an array, individual probes typically are immobilized at separate locations and allowed to react for binding reactions. Primers associated with assembled sets of markers are useful for either preparing libraries of sequences or directly detecting markers from other biological samples.

A library (or array, when referring to physically separated nucleic acids corresponding to at least some sequences in a library) of gene markers exhibits highly desirable properties. These properties are associated with specific conditions, and may be characterized as regulatory profiles. A profile, as termed here refers to a set of members that provides diagnostic information of the tissue from which the markers were originally derived. A profile in many instances comprises a series of spots on an array made from deposited sequences.

A characteristic patient profile is generally prepared by use of an array. An array profile may be compared with one or more other array profiles or other reference profiles. The comparative results can provide rich information pertaining to disease states, developmental state, receptiveness to therapy and other information about the patient.

Another aspect of the present invention provides a diagnostic kit for assaying biological samples comprising an agent for detecting one or more neoplastic markers and reagents useful for facilitating the detection by said agent. Further means may also be included, for example, to receive a biological sample. The agent may be any suitable detecting molecule.

The present invention is further described by the following non-limiting examples:

Example 1 Methods and Materials Affymetrix GeneChip Data

Gene expression profiling data and accompanying clinical data was purchased from GeneLogic Inc (Gaithersburg, Md. USA). For each tissue analyzed, oligonucleotide microarray data for 44,928 probesets (Affymetrix HGU133A & HGU133B, combined), experimental and clinical descriptors, and digitally archived microscopy images of histological preparations were received. A quality control analysis was performed to remove arrays not meeting essential quality control measures as defined by the manufacturer.

Transcript expression levels were calculated by both Microarray Suite (MAS) 5.0 (Affymetrix) and the Robust Multichip Average (RMA) normalization techniques (Affymetrix. GeneChip expression data analysis fundamentals. Affymetrix, Santa Clara, Calif. USA, 2001; Hubbell et al. Bioinformatics, 18:1585-1592, 2002; Irizarry et al. Nucleic Acid Research, 31, 2003) MAS normalized data was used for performing standard quality control routines and the final data set was normalized with RMA for all subsequent analyses.

Univariate Differential Expression

Differentially expressed gene transcripts were identified using a moderated t-test implemented in the limma library downloaded from the Bioconductor repository for R. (G. K. Smyth. Statistical Applications in Genetics and Molecular Biology, 3(1):Article 3, 2004; G K Smyth. Bioinformatics and Computational Biology Solutions using R and Bioconductor. Springer, New York, 2005). Significance estimates (p-values) were corrected to adjust for multiple hypothesis testing using the Bonferonni correction.

Tissue Specific Expression Patterns

To construct a filter for hypothetically ‘turned on’ gene expression the mean expression level for all 44,928 probesets across the full range of 454 tissues was first estimated. To estimate an expression on/off threshold, the 44,928 mean values were ranked and the expression value equivalent to the 30th percentile across the dataset calculated. This arbitrary threshold was chosen because it was theorized that the majority of transcripts (and presumably more than 30%) in a given specimen should be transcriptionally silenced. Thus this threshold represents a conservative upper bound for what is estimated as non-specific, or background, signal.

Gene Symbol Annotations

To map Affymetrix probeset names to official gene symbols the annotation metadata available from Bioconductor was used. hgu133plus2 library version 1.16.0, which was assembled using Entrez Gene data downloaded on 15 Mar. 2007, was used.

Estimates of Performance Characteristics

Diagnostic utility for each table of markers shown herein was estimated including: sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratio positive, likelihood ratio negative. These estimates were calculated in the same data used to discover the markers and will therefore potentially overestimate the performance characteristics in future tissue samples. To improve the generalisabilty of the estimates a modified jackknife resampling technique was used to calculate a less biased value for each characteristic.

Results

A range of univariate statistical tests were applied on Affymetrix oligonucleotide microarray data to reveal human genes that could be used to discriminate colorectal neoplastic tissues from non-neoplastic tissues. There were further identified a number of gene transcripts that appear to be useful for differentiating colorectal adenomas from colorectal carcinoma. Also identified were a subset of these transcripts that may have particular diagnostic utility because due to the protein products being either secreted or displayed on the cell surface of epithelial cells. Finally, there were identified a further subset of transcripts expressed specifically in neoplastic tissues and at low- or near-background levels in non-neoplastic tissues.

Genes Differentially Expressed in Neoplastic Tissues

From a total GeneChip set of 44,928 probesets it was determined that over 11,000 probesets were differentially expressed by moderated t-test using the limma package in BioConductor (G. K. Smyth, 2004 supra) employing conservative (Bonferroni) multiple test correction. When this list was further filtered to include only those probesets demonstrating a 2-fold or greater mean expression change between the neoplastic and non-neoplastic tissues, 206 probesets were found to be expressed higher in neoplasias relative to normals.

These 205 probesets were annotated using the most recent metadata and annotation packages available for the chips. The 205 overexpressed probesets were mapped to 174 gene symbols.

Δ-expression ProbeSet ID Gene Symbol Maps UP 205 157

Hypothetical Markers Specific for Colorectal Neoplasia

While differential gene expression patterns are useful for diagnostic purposes, this project also seeks to identify diagnostic proteins shed into the lumen of the gut by neoplastic colorectal epithelia. To discover candidate proteins the list of differentially expressed transcripts were filtered with a selection criteria aimed at identifying markers specifically expressed in colorectal neoplasia tissues. This filter criteria is based on a theoretical assumption that most genes on the GeneChip will be turned ‘off’ and that any microarray signals for such ‘off’ transcripts will reflect technical assay background and non-specific oligonucleotide binding. Accordingly, to select genes specifically expressed in neoplastic tumours (i.e. ‘on’) the non-neoplastic signals were compared with a hypothetical background signal threshold from across all genes on the chip. By design, all transcripts in the candidate pool from which the ‘on’ transcripts are chosen are at least two fold overexpressed in the diseased tissues. Combined, it is hypothesized that these criteria yield the subset of differentially expressed genes that are specifically expressed in neoplasia. The expression profile for a representative ‘on’ transcript is shown in FIG. 1.

Genes Differentially Expressed Between Adenomas and Cancer Tissues

There were 33 transcripts observed that were differentially expressed at least two-fold higher in adenoma tissues relative to cancer tissues. In particular, there were identified several transcripts that exhibit an expression pattern specific for adenomas, including SLITRK6 and L1TD1, shown in FIG. 2.

Further, there were also identified cancer specific transcripts. The expression profile of one such transcript, COL11A1 is shown in FIG. 3.

Example 2 Probesets Elevated In Neoplasia

Differential expression analysis was applied to Affymetrix gene chip data measuring RNA concentration in 454 colorectal tissues including 161 adenocarcinoma specimens, 29 adenoma specimens, 42 colitis specimens and 222 non-diseased tissues. Using conservative corrections for multiple hypothesis testing, it was determined that over 25% of the 44,928 probesets measured in each tissue experiment were differentially expressed between the 190 neoplasia specimens and 264 non-neoplasia controls. To identify robust biomarkers for colorectal neoplasia the list of putative probeset biomarkers were further filtered to include only those probesets shown to be expressed at least 2-fold higher in neoplastic vs. non-neoplastic tissues.

205 probesets hybridising to approximately 157 putative genes were observed to be expressed at a statistically significant higher level in neoplastic tissues relative to non-neoplastic controls.

Validation/Hypothesis Testing

To validate these discovery results the hybridisation of 199 candidate probesets were measured against RNA extracts from 68 clinical specimens comprising 19 adenomas, 19 adenocarcinomas, and 30 non-diseased controls using a custom-designed ‘Adenoma Gene Chip’. Six (6) probesets were not tested as they were not included on the custom design. It was confirmed that 186/199 (88%) of the target probesets or probesets which also hybridise to the target locus were likewise differentially expressed (P<0.05) in these independently-derived tissues. The results of testing these probesets in 68 independently collected clinical specimens is shown in Table 1.

We further tested the 142 of the 157 unique gene loci to which the 205 probesets are understood to hybridise. We note the remaining 15 gene symbols were not represented in the validation data. We observed that 133 of 142 gene symbols were represented in the validation data by at least one differentially expressed probeset and many symbols included multiple probesets against regions across the putative locus. A complete list of probesets that bind to target loci is shown in Table 2.

Conclusion

The candidate probesets shown in Tables 1 and 2 are differentially expressed in neoplastic colorectal tissues compared to non-neoplastic controls.

Example 3 Probesets Demonstrating A Neoplasia-Specific Profile

During analysis of the data, a novel expression profile was observed between neoplastic and non-neoplastic phenotypes. It was hypothesized that a subset of quantitatively differentially expressed probesets are furthermore qualitatively differentially expressed. Such probesets show evidence of a neoplasia-specific gene expression profile, i.e. these probesets appear to be expressed above background levels in neoplastic tissues only. This observation and the resulting hypothesis are based on two principles:

-   1. That the majority of human transcripts that are present on a     genome-wide GeneChip (e.g. U133) will not likely be expressed in the     colorectal mucosa; and -   2. That microarray binding intensity for such ‘off’ probesets to     labelled cRNA will reflect technical assay background, i.e.     non-specific oligonucleotide binding.

To generate a list of neoplasia specific probesets the non-neoplastic intensity of differentially expressed probesets was compared with a hypothetical background signal threshold from across all probesets on the chip. Bydesign, all probesets in the candidate pool from which the ‘on’ transcripts are chosen are at least two fold over-expressed in the diseased tissues. Combined, these criteria yield the subset of differentially expressed transcript species that are specifically expressed in neoplasia.

Validation/Hypothesis Testing

The custom gene chip design precludes testing the hypothetically neoplasia-specific probesets using the same principles as used for discovery. In particular, the custom gene chip (by design) does not contain a large pool of probesets anticipated to hybridise to hypothetically ‘off’/‘non-transcribed’ gene transcripts. This is because the custom gene chip design is biased toward differentially expressed transcripts in colorectal neoplastic tissues.

The usual differential expression testing (limma) was therefore to these candidate probesets for neoplasia-specific transcripts. Of the 33 probesets on the custom gene chip, 32 probesets (or probesets which bind to the same locus) were differentially expressed between the 38 neoplastic tissues (adenoma & cancer) and non-neoplastic controls. The results of these validation experiments is shown in Table 3.

All probesets which are known to hybridise to the gene loci to which the 33 probesets claimed herein were tested. Of the 32 putative gene loci targeted by the probesets, 29 were present in the validation data. Twenty-eight (28) of these 29 gene symbols demonstrated at least one hybridising probeset which was differentially expressed in the neoplastic tissues. Results for these experiments, including all probesets that bind to each target locus in a differentially expressed manner are shown in Table 4.

Example 4 Probesets Useful for Characterizing Neoplastic Tissues

Differential expression analysis was applied to Affymetrix gene chip data measuring RNA concentration in neoplastic tissues including 161 adenocarcinoma specimens and 29 adenoma specimens. It was observed that 43 probesets hybridizing to approximately 33 putative gene symbols were expressed higher (P<0.05) in adenoma tissues relative to cancer tissues. Conversely, 145 probesets (104 gene symbols) were identified to be expressed higher in cancer relative to adenomas.

Validation/Hypothesis Testing

188 (43+145) of these probesets were then measured in a set of independent clinical specimens including 19 adenoma tissues and 19 cancer tissues. It was confirmed that 158 (30+128) of the target probesets (or probesets against the same gene locus) were likewise differentially expressed (P<0.05) in these independently-derived tissues. Probesets elevated in adenoma and cancers relative to each other are shown in Table 5 and Table 6 respectively.

It was further observed that 137 (33+104) gene loci are diagnostically useful for discriminating colorectal adenomas and cancers relative to each phenotype. The validation data included probesets designed to hybridise to 128 of these candidate gene symbols. It was observed that 21 of the 31 genes elevated in adenomas relative to cancers were likewise differentially expressed by at least one probeset. Of the 97 gene symbols elevated in cancer relative to adenoma it was confirmed that 89 gene symbols demonstrated at least one probeset in the validation data to be likewise differentially expressed. The validation testing of the adenoma and cancer elevated gene loci is shown in Table 7 and Table 8, respectively.

Conclusion

It was concluded that the candidate probesets shown in FIXME are differentially expressed between adenomatous and adenocarcinoma tissues and thus useful for distinguishing these tissues. Gene transcripts that hybridise to these probesets are thus diagnostically informative in a clinical setting to classify such neoplastic tissues.

Example 5 Materials and Methods for Examples 2 to 3

Gene expression profiling data measured in 454 colorectal tissue specimens including neoplastic, normal and non-neoplastic disease controls was purchased from GeneLogic Inc (Gaithersburg, Md. USA). For each tissue specimen an Affymetrix (Santa Clara, Calif. USA) oligonucleotide microarray data totalling 44,928 probesets (HGU133A & HGU133B, combined), experimental and clinical descriptors, and digitally archived microscopy images of histological preparations was received. Prior to applying discovery methods to these data extensive quality control methods were carried out, including statistical exploration, review of clinical records for consistency and histopathology audit of a random sample of arrays. Microarrays that did not meet acceptable quality criteria were removed from the analysis.

Hypothesis Testing

Candidate transcription biomarkers were tested using a custom oligonucleotide microarray of 25-mer oligonucleotide probesets designed to hybridise to candidate RNA transcripts identified during discovery. Differential expression hypotheses were tested using RNA extracts derived from independently collected clinical samples comprising 30 normal colorectal tissues, 19 colorectal adenoma tissues, and 19 colorectal adenocarcinoma tissues. Each RNA extract was confirmed to meet strict quality control criteria.

Colorectal Tissue Specimens

All tissues used for hypothesis testing were obtained from a tertiary referral hospital tissue bank in metropolitan Adelaide, Australia (Repatriation General Hospital and Flinders Medical Centre). Access to the tissue bank for this research was approved by the Research and Ethics Committee of the Repatriation General Hospital and the Ethics Committee of Flinders Medical Centre. Informed patient consent was received for each tissue studied.

Following surgical resection, specimens were placed in a sterile receptacle and collected from theatre. The time from operative resection to collection from theatre was variable but not more than 30 minutes. Samples, approximately 125 mm3 (5×5×5 mm) in size, were taken from the macroscopically normal tissue as far from pathology as possible, defined both by colonic region as well as by distance either proximal or distal to the pathology. Tissues were placed in cryovials, then immediately immersed in liquid nitrogen and stored at −150 C until processing.

RNA Extraction

RNA extractions were performed using Trizol(R) reagent (Invitrogen, Carlsbad, Calif., USA) as per manufacturer's instructions. Each sample was homogenised in 300 μL of Trizol reagent using a modified Dremel drill and sterilised disposable pestles. An additional 200 μL of Trizol reagent was added to the homogenate and samples were incubated at RT for 10 minutes. 100 μL of chloroform was then added, samples were shaken vortexed for 15 seconds, and incubated at RT for 3 further minutes. The aqueous phase containing target RNA was obtained by centrifugation at 12,000 rpm for 15 min, 40 C. RNA was then precipitated by incubating samples at RT for 10 min with 250 μL of isopropanol. Purified RNA precipitate was collected by centrifugation at 12,000 rpm for 10 minutes, 40 C and supernatants were discarded. Pellets were then washed with 1 mL 75% ethanol, followed by vortexing and centrifugation at 7,500 g for 8 min, 40 C. Finally, pellets were air-dried for 5 min and resuspended in 80 μL of RNase free water. To improve subsequent solubility samples were incubated at 55° C. for 10 min. RNA was quantified by measuring the optical density at A260/280 nm. RNA quality was assessed by electrophoresis on a 1.2% agarose formaldehyde gel.

Gene Chip Processing

To test hypotheses related to biomarker candidates for colorectal neoplasia RNA extracts were assayed using a custom GeneChip designed in collaboration with Affymetrix (Santa Clara, Calif. USA). These custom GeneChips were processed using the standard Affymetrix protocol developed for the HU Gene ST 1.0 array described in (Affy:WTAssay).

Statistical Software and Data Processing

The R statistics environment R and BioConductor libraries (BioConductor, www.bioconductor.org) (BIOC) were used for most analyses. To map probeset IDs to gene symbol on the Custom GeneChip, hgu133plus2 library version 2.2.0, which was assembled using Entrez Gene data downloaded on April 18 12:30:55 2008 (BIOC) was used.

Hypothesis Testing of Differentially Expressed Biomarkers

To assess differential expression between tissue classes, the Student's t test for equal means between two samples or the robust variant provided by the limma library (Smyth)(limma) was used. The impact of false discovery due to multiple hypothesis testing was mitigated by applying a Bonferroni adjustment to P values in the discovery process (MHT:Bonf). For hypotheses testing the slightly less conservative multiple hypothesis testing correction of Benjamini & Hochberg, which aims to control the false discovery rate of solutions (MHT:BH) was applied.

Discovery of Tissue-Specific Gene Expression Patterns

Discovery methods using gene expression data often yield numerous candidates, many of which are not suitable for commercial products because they involve subtle gene expression differences that would be difficult to detect in laboratory practice. Pepe et al. note that the ‘ideal’ biomarker is detectable in tumor tissue but not detectable (at all) in non-tumour tissue (Pepe:biomarker:development.) To bias toward candidates that meet this criterion, an analysis method was developed that aims to enrich the candidates for biomarkers whose qualitative absence or presence measurement is diagnostic for the phenotype of interest. This method attempts to select candidates that show a prototypical ‘turned-on’ or ‘turned-off’ pattern relative to an estimate of the background/noise expression across the chip. Such RNA transcripts are more likely to correlate with downstream translated proteins with diagnostic potential or to predict upstream genomic changes (e.g. methylation status) that can be used diagnostically. This focus on qualitative rather than quantitative outcomes may simplify the product development process for such biomarkers.

The method is based on the assumption that the pool of extracted RNA species in any given tissue (e.g. colorectal mucosae) will specifically bind to a relatively small subset of the full set of probesets on a GeneChip designed to measure the whole genome. On this assumption, it is estimated that most probesets on a full human gene chip will not exhibit specific, high-intensity signals.

This observation is utilised to approximate the background or ‘non-specific binding’ across the chip by choosing a theoretical level equal to the value of e.g. lowest 30% quantile of the ranked mean values. This quantile can be arbitrarily set to some level below which a reasonable assumption is made that the signals do not represent above-background RNA binding. Finally, this background estimate is used as a threshold to estimate the ‘OFF’ probesets in an experiment for, say, the non-neoplastic tissue specimens. Conversely, probesets which are 1) expressed above this theoretical threshold level and 2) at differentially higher levels in the tumour specimens may be a tumour specific candidate biomarker. In this case the concept of ‘fold-change’ thresholds can also be conveniently applied to further emphasize the concept of absolute expression increases in a putatively ‘ON’ probeset.

Given the assumption of low background binding for a sizeable fraction of the measured probesets, this method was only used in the large GeneLogic data and discovery. To construct a filter for hypothetically ‘turned on’ biomarkers in the GeneLogic discovery data, the mean expression level for all 44,928 probesets was first estimated across the full range of 454 tissues. The 44,928 mean values were then ranked and the expression value equivalent to the 25th percentile across the dataset calculated. This arbitrary threshold was chosen because it was theorized that the majority of transcripts (and presumably more than 25%) in a given specimen should exhibit low concentration which effectively transcriptional silence. Thus this threshold represents a conservative upper bound for what is estimated as non-specific, or background, expression.

Example 6 Determine Gene Identity of a Nucleic Acid Sequence of Interest which is Define by an Affymetrix Probeset

BLAST the sequence of interest using online available Basic Local Alignment Search Tools [BLAST]. e.g. NCBI/BLAST

-   -   (http://blast.ncbi.nlm.nih.gov/Blast.cgi)

-   (a) Select “Human” in BLAST ASSEMBLED GENOMES on the web page     http://blast.ncbi.nlm.nih.gov/Blast.cgi

-   (b) Leave the default settings, i.e.:     -   Database: Genome (all assemblies)     -   Program: megaBLAST: compare highly related nucleotide sequences     -   Optional parameters: Expect: 0.01, Filter: default,         Descriptions: 100, Alignments: 100

-   (c) Copy/Paste Sequence into the “BLAST” window

-   (d) Click “Begin Search”

-   (e) Click “View Report”

Assessment of the Open BLAST Search Results

Multiple significant sequence alignments may be identified when “blasting” the sequence.

Identify Gene Nomenclature of the Identified Sequence Match

-   (a) Click the link to one of the identified hits -   (b) The new page will schematically depict the position of the hit     on one chromosome. It will be apparent which gene is hit. -   (c) Retrieve the “hit” sequence clicking on the link -   (d) Do a search for the gene in the provided “search” window. This     provides the gene nucleotide coordinates for the gene.

Determine Promiscuity of Sequence

-   (a) Open the NCBI/BLAST tool,     (http://blast.ncbi.nlm.nih.gov/Blast.cgi) -   (b) Click on “nucleotide Blast” under “basic BLAST” -   (c) Copy/paste the sequence of interest into the “Query Sequence”     window -   (d) Click “Blast”.     Assessment of the nBLAST Search Results of the Sequence -   (a) The nBLAST exercise with the Sequence may result in multiple     Blast hits of which some accession entry numbers are listed in     “Description”. -   (b) These hits should be reviewed.

Determine Location of the Sequence in the Gene

The Ensembl database is an online database, which produces and maintains automatic annotation selected eukaryotic genomes (www.ensembl.org/index.html)

Identify Location of the Sequence in the Gene

-   (a) Set “Search” to Homo Sapiens, Type “the gene name” in the     provided Search Field Ensemble.org/index.html) -   (b) Click “Go” -   (c) Click the “vega protein coding Gene: OTTHUMG000000144184” link     to get an annotation report -   (d) Click on “Gene DAS Report” to retrieve information regarding     Alternative splice site database: Type “the gene name” in search     field     -   Click on “the gene entry”     -   Scroll down to “evidence”     -   Review alternative splice sites     -   Click “Confirmed intron/exons” to get a list of coordinates for         the exons & introns.         Alternative Splicing and/or Transcription

The AceView Database provides curated and non-redundant sequence representation of all public mRNA sequences. The database is available through NCBI: http://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/

Further Investigation of the Gene mRNA Transcripts

-   (a) Type “the gene name” into the provided “search” field -   (b) Click “Go” -   (c) The following information is available from the resulting entry     in AceView:     -   The number of cDNA clones from which the gene is constructed (ie         originated-from experimental work involving isolation of mRNA)     -   The mRNAs predicted to be produced by the gene     -   The existence of non-overlapping alternative exons and validated         alternative polyadenylation sites     -   The existence of truncations     -   The possibility of regulated alternate expression     -   Introns recorded as participating in alternatively splicing of         the gene -   (d) Classic splice site motives

Materials and Methods Extraction of RNA

RNA extractions were performed using Trizol(R) reagent (Invitrogen, Carlsbad, Calif., USA) as per manufacturer's instructions. Each sample was homogenised in 300 μL of Trizol reagent using a modified dremel drill and sterilised disposable pestles. Additional 200 μL of Trizol reagent was added to the homogenate and samples were incubated at RT for 10 minutes. 100 μL of chloroform was then added, samples were shaken vortexed for 15 seconds, and incubated at RT for 3 further minutes. The aqueous phase containing target RNA was obtained by centrifugation at 12,000 rpm for 15 min, 40. C. RNA was then precipitated by incubating samples at RT for 10 min with 250 μL of isopropanol. Purified RNA precipitate was collected by centrifugation at 12,000 rpm for 10 minutes, 40. C and supernatants were discarded. Pellets were then washed with 1 mL 75% ethanol, followed by vortexing and centrifugation at 7,500 g for 8 min, 40. C. Finally, pellets were air-dried for 5 min and resuspended in 80 μL of RNase free water. To improve subsequent solubility samples were incubated at 55. C for 10 min. RNA was quantified by measuring the optical density at A260/280 nm. RNA quality was assessed by electrophoresis on a 1.2% agarose formaldehyde gel.

Gene Chip Processing

RNA samples to analyze on Human Exon 1.0 ST GeneChips were processed using the Affymetrix WT target labeling and control kit (part#900652) following the protocol described in (Affymetrix 2007 P/N 701880 Rev.4). Briefly: First cycle cDNA was synthesized from 100 ng ribosomal reduced RNA using random hexamer primers tagged with T7 promoter sequence and SuperScript II (Invitrogen, Carlsbad Calif.), this was followed by DNA Polymerase I synthesis of the second strand cDNA. Anti-sense cRNA was then synthesized using T7 polymerase. Second cycle sense cDNA was then synthesised using SuperScript II, dNTP+dUTP, and random hexamers to produce sense strand cDNA incorporating uracil. This single stranded uracil containing cDNA was then fragmented using a combination of uracil DNA glycosylase (UDG) and apurinic/apyrimidinic endonuclease1 (APE 1). Finally the DNA was biotin labelled using terminal deoxynucleotidyl transferase (TdT) and the Affymetrix proprietary DNA Labeling reagent. Hybridization to the arrays was carried out at 45° C. for 16-18 hours.

Washing and staining of the hybridized GeneChips was carried out using the Affymetrix Fluidics Station 450 and scanned with the Affymetrix Scanner 3000 following recommended protocols.

SYBR Green Based Quantitative Real Time-PCR

Quantitative real time polymerase chain reaction was performed on RNA isolated from clinical samples for the amplification and detection of the various hCG_1815491 transcripts.

Firstly cDNA was synthesized from 2 ug of total RNA using the Applied Biosystems High Capacity Reverse transcription Kit (P/N 4368814). After synthesis the reaction was diluted 1:2 with water to obtain a final volume of 40 ul and 1 ul of this diluted cDNA used in subsequent PCR reactions.

PCR was performed in a 25 ul volume using 12.5 ul Promega 2×PCR master mix (P/N M7502), 1.5 ul 5 uM forward primer, 1.5 ul 5 uM reverse primer, 7.875 ul water, 0.625 ul of a 1:3000 dilution of 10,000× stock of SYBR green 1 pure dye (Invitrogen P/N S7567), and 1 ul of cDNA.

Cycling conditions for amplification were 95° for 2 minutes ×1 cycle, 95° for 15 seconds and 60° for 1 minute ×40 cycles. The amplification reactions were performed in a Corbett Research Rotor-Gene RG3000 or a Roche LightCycler480 real-time PCR machine. When the Roche LightCycler480 real-time PCR machine was used for amplification the reaction volume was reduced to 10 ul and performed in a 384 well plate but the relative ratios between all the components remained the same. Final results were calculated using the ΔΔCt method with the expression levels of the various hCG_1815491 transcripts being calculated relative to the expression level of the endogenous house keeping gene HPRT.

End-Point PCR

End point PCR was performed on RNA isolated from clinical samples for the various hCG 1815491 transcripts. Conditions were identical to those described for the SYBR green assay above but with the SYBR green dye being replaced with water. The amplification reactions were performed in a MJ Research PTC-200 thermal cycler. 2.5411 of the amplified products were analysed on 2% agarose E-gel (Invitrogen) along with a 100-base pair DNA Ladder Marker.

Results

The nucleotide structure and expression levels of transcripts related to hCG_1815491 was analysed based on the identification of diagnostic utility of Affymetrix probesets 238021_s at and 238022_at from the gene chip analysis.

The gene hCG_1815491 is currently represented in NCBI as a single RefSeq sequence, XM_93911. The RefSeq sequence of hCG_1815491 is based on 89 GenBank accessions from 83 cDNA clones. Prior to March 2006, these clones were predicted to represent two overlapping genes, LOC388279 and LOC650242 (the latter also known as LOC643911). In March 2006, the human genome database was filtered against clone rearrangements, co-aligned with the genome and clustered in a minimal non-redundant way. As a result, LOC388272 and LOC650242 were merged into one gene named hCG_1815491 (earlier references to hCG_1815491 are: LOC388279, LOC643911, LOC650242, XM_944116, AF275804, XM_373688).

It has been determined that the Ref Sequence, which is defined by the genomic coordinates 8579310 to 8562303 on human chromosome 16 as defined by the NCBI contig reference NT_010498.15|Hs16_10655, NCBI 36 March 2006 genome encompasses hCG_1815491. The 10 predicted RNA variants derived from this gene have been aligned with the genomic nucleotide sequence residing in the map region 8579310 to 8562303. This alignment analysis revealed the existence of at least 6 exons of which several are alternatively spliced. The identified exons are in contrast to the just 4 exons specified in the NCBI hCG_1815491 RefSeq XM_93911. Two additional putative exons were also identified in the Ref Sequence by examination of included probesets on Affymetrix Genechip HuGene Exon 1.0 that target nucleotide sequences embedded in the Ref Sequence. The identified and expanded exon-intron structure of hCG_1815491 have been used to design specific oligonucleotide primers, which allowed measurement of the expression of RNA variants generated from the Ref Sequence by using PCR-based methodology (FIG. 4)

Example 7

Immunohistochemistry is a useful method for evaluating changes in local expression of up or down-regulated markers in human tissue.

Materials and Methods:

Four micrometre sections were incubated in a universal decloaking buffer for 75 minutes at 80 μL to expose masked epitopes. Protein expression was determined using an antibody targeting the C-terminal domain of Mesothelin (MSLN) on colonic biopsies from 30 patients (10 normals, 10 cancers, 10 adenomas). Antibodies were applied for one hour at room temperature. After washing, sections were incubated with polymeric horse-radish peroxidase. Antibody localization was visualized using 3′3′ diaminobenzidine.

Result:

There was a marked upregulation of MSLN in the adenoma and cancer tissues compared to the normal controls. The normal tissues showed mild staining for MSLN in the cytoplasm of the colonic epithelium but the cancer and particularly the adenomas tissues shows significant upregulation of MSLN in their multilayered epithelium. This upregulation was observed in all 10 adenomas tissue and in 9 out of the 10 cancer tissues. These patterns of staining are illustrated in FIGS. 4, 5 and 6.

Conclusion:

Elevated expression of MSLN has been detected in colon neoplasia, confirming the upregulation observed in the mRNA expression data and verifying the diagnostic utility of both the MSLN mRNA and protein for detection of colorectal neoplasia.

Example 8 Evidence of MMP3 Protein Expression in Stools of Patients with Colorectal Neoplasia

Affymetrix probeset designated 205828_at was identified to be expressed higher in 190 neoplastic tissue specimens relative to 264 non-neoplastic specimens. The probeset 205828_at hybridizes to RNA transcribed from the gene encoding Matrix Metalloproteinase 3 (MMP3) NM_002422. The differential expression profile of probeset 205828_at was further demonstrated by profiling RNA collected from 68 independent clinical specimens comprising 19 adenomas, 19 adenocarcinomas and 30 non-disease controls, FIG. 7.

Materials and Methods

A commercially available bead-suspension immunoassay targeting the protein MMP3 was purchased from R&D Systems (MMP Kit reagents LMP000 and LMP513) to measure MMP3 concentration in stools of human patients diagnosed with colorectal neoplasia. Proteins were extracted from stool specimens using a phosphate buffered saline wash from 6 non-disease controls, 10 adenoma and 11 adenocarcinoma subjects. The resulting protein extracts were analyzed using the Luminex bead-based suspension MMP3 assay as recommended by manufacturer.

Results

An elevated endogenous expression of MMP3 was observed in stool specimens from patients diagnosed with colon adenomas or adenocarcinomas relative to non-neoplastic controls (FIG. 8).

Conclusion

Measurement of MMP3 protein in bodily fluids such as stool samples is useful for diagnosing colorectal neoplasia.

Tables

Probeset designations include both HG-133plus2 probeset IDs and Human Gene 1.0ST array probe ids. The latter can be conveniently mapped to Transcript Cluster ID using the Human Gene 1.0ST probe tab file provided by Affymetrix (http://www.affymetrix.com/Auth/analysis/downloads/na22/wtgene/HuGene-1 0-st-v1.probe.tab.zip). Using publicly available software such as NetAffx (provided by Affymetrix), the Transcript Cluster ID may be further mapped to gene symbol, chromosomal location, etc.

Table 1.

Probesets demonstrated to be expressed higher in neoplastic tissues relative to non-neoplastic controls. TargetPS: Affymetrix HG-U133plus2 probeset id; Symbol: putative gene symbol corresponding to target probeset id—multiple symbol names indicate the possibility of probeset hybridisation to multiple gene targets; Signif. FDR: Adjusted p-value for mean difference testing between RNA extracted from neoplasia and non-neoplastic tissues. Adjustment is made using Benjamini & Hochberg correction for multiple hypothesis testing (Benjamini and Hochberg, 1995); D.value50: Diagnostic effectiveness parameter estimate corresponding to the area of a receiver operator characteristic ROC. This parameter provides a convenient estimate of diagnostic utility and is described in (Saunders, 2006); FC: fold change between mean expression level of neoplasia vs. non-neoplasia; Sens-Spec: Estimate of diagnostic performance corresponding to the ROC curve point demonstrating equal sensitivity and specificity; CI (95): 95% confidence interval of sensitivity and specificity estimates.

Table 2.

Evidence of multiple probesets which correspond to gene symbols claimed herein exhibiting RNA concentration differences between neoplasia and non-neoplastic controls. Symbol: gene symbol; ValidPS_UP: Affymetrix probeset IDs demonstrating statistically significant overexpression in neoplastic RNA extracts relative to non-neoplastic controls. Signif. FDR: Adjusted p-value for mean difference testing between RNA extracted from neoplasia and non-neoplastic tissues. Adjustment is made using Benjamini & Hochberg correction for multiple hypothesis testing (Benjamini and Hochberg, 1995); D.value50: Diagnostic effectiveness parameter estimate corresponding to the area of a receiver operator characteristic ROC. This parameter provides a convenient estimate of diagnostic utility and is described in (Saunders, 2006); FC: fold change between mean expression level of neoplasia vs. non-neoplasia; Sens-Spec: Estimate of diagnostic performance corresponding to the ROC curve point demonstrating equal sensitivity and specificity; CI (95): 95% confidence interval of sensitivity and specificity estimates.

Example 2 Table 3.

Probesets which demonstrate a qualitatively (in addition to quantitative) elevated profile in neoplastic tissues relative to non-neoplastic controls. TargetPS: Affymetrix HG-U133plus2 probeset id; Symbol: putative gene symbol corresponding to target probeset id—multiple symbol names indicate the possibility of probeset hybridisation to multiple gene targets; Signif. FDR: Adjusted p-value for mean difference testing between RNA extracted from neoplasia and non-neoplastic tissues. Adjustment is made using Benjamini & Hochberg correction for multiple hypothesis testing (Benjamini and Hochberg, 1995); D.value50: Diagnostic effectiveness parameter estimate corresponding to the area of a receiver operator characteristic ROC. This parameter provides a convenient estimate of diagnostic utility and is described in (Saunders, 2006); FC: fold change between mean expression level of neoplasia vs. non-neoplasia; Sens-Spec: Estimate of diagnostic performance corresponding to the ROC curve point demonstrating equal sensitivity and specificity; CI (95): 95% confidence interval of sensitivity and specificity estimates.

Table 4.

Evidence of multiple probesets which correspond to gene symbols claimed herein exhibiting qualitative changes in RNA concentration in neoplastic tissues. Symbol: gene symbol; ValidPS_UP: Affymetrix probeset IDs demonstrating statistically significant overexpression in neoplastic RNA extracts relative to non-neoplastic controls. Signif. FDR: Adjusted p-value for mean difference testing between RNA extracted from neoplasia and non-neoplastic tissues. Adjustment is made using Benjamini & Hochberg correction for multiple hypothesis testing (Benjamini and Hochberg, 1995); D.value50: Diagnostic effectiveness parameter estimate corresponding to the area of a receiver operator characteristic ROC. This parameter provides a convenient estimate of diagnostic utility and is described in (Saunders, 2006); FC: fold change between mean expression level of neoplasia vs. non-neoplasia; Sens-Spec: Estimate of diagnostic performance corresponding to the ROC curve point demonstrating equal sensitivity and specificity; CI (95): 95% confidence interval of sensitivity and specificity estimates.

Table 5

Probesets demonstrated to be expressed higher in adenoma tissues relative to cancer tissues. TargetPS: Affymetrix HG-U133plus2 probeset id; Symbol: putative gene symbol corresponding to target probeset id—multiple symbol names indicate the possibility of probeset hybridisation to multiple gene targets; Signif. FDR: Adjusted p-value for mean difference testing between RNA extracted from neoplasia and non-neoplastic tissues. Adjustment is made using Benjamini &

Hochberg correction for multiple hypothesis testing (Benjamini and Hochberg, 1995); D.value50: Diagnostic effectiveness parameter estimate corresponding to the area of a receiver operator characteristic ROC. This parameter provides a convenient estimate of diagnostic utility and is described in (Saunders, 2006); FC: fold change between mean expression level of adenomas vs. cancers; Sens-Spec: Estimate of diagnostic performance corresponding to the ROC curve point demonstrating equal sensitivity and specificity; CI (95): 95% confidence interval of sensitivity and specificity estimates.

Table 6 Probesets demonstrated to be expressed higher in cancer tissues relative to adenoma tissues. TargetPS: Affymetrix HG-U133plus2 probeset id; Symbol: putative gene symbol corresponding to target probeset id—multiple symbol names indicate the possibility of probeset hybridisation to multiple gene targets; Signif. FDR: Adjusted p-value for mean difference testing between RNA extracted from neoplasia and non-neoplastic tissues. Adjustment is made using Benjamini & Hochberg correction for multiple hypothesis testing (Benjamini and Hochberg, 1995); D.value50: Diagnostic effectiveness parameter estimate corresponding to the area of a receiver operator characteristic ROC. This parameter provides a convenient estimate of diagnostic utility and is described in (Saunders, 2006); FC: fold change between mean expression level of cancer tissues vs. adenoma tissues; Sens-Spec: Estimate of diagnostic performance corresponding to the ROC curve point demonstrating equal sensitivity and specificity; CI (95): 95% confidence interval of sensitivity and specificity estimates.

Table 7

Evidence of multiple probesets which correspond to gene symbols claimed herein exhibiting

RNA concentration differences between adenoma and cancer tissues. Symbol: gene symbol; ValidPS_UP: Affymetrix probeset IDs demonstrating statistically significant overexpression in neoplastic RNA extracts relative to non-neoplastic controls. Signif. FDR: Adjusted p-value for mean difference testing between RNA extracted from neoplasia and non-neoplastic tissues. Adjustment is made using Benjamini & Hochberg correction for multiple hypothesis testing (Benjamini and Hochberg, 1995); D.value50: Diagnostic effectiveness parameter estimate corresponding to the area of a receiver operator characteristic ROC. This parameter provides a convenient estimate of diagnostic utility and is described in (Saunders, 2006); FC: fold change between mean expression level of adenoma tissues vs. cancer tissues; Sens-Spec: Estimate of diagnostic performance corresponding to the ROC curve point demonstrating equal sensitivity and specificity; CI (95): 95% confidence interval of sensitivity and specificity estimates.

Table 8

Evidence of multiple probesets which correspond to gene symbols claimed herein exhibiting

RNA concentration differences between cancer and adenoma tissues. Symbol: gene symbol; ValidPS_UP: Affymetrix probeset IDs demonstrating statistically significant overexpression in neoplastic RNA extracts relative to non-neoplastic controls. Signif. FDR: Adjusted p-value for mean difference testing between RNA extracted from neoplasia and non-neoplastic tissues. Adjustment is made using Benjamini & Hochberg correction for multiple hypothesis testing

(Benjamini and Hochberg, 1995); D.value50: Diagnostic effectiveness parameter estimate corresponding to the area of a receiver operator characteristic ROC. This parameter provides a convenient estimate of diagnostic utility and is described in (Saunders, 2006); FC: fold change between mean expression level of cancer tissues vs. adenoma tissues; Sens-Spec: Estimate of diagnostic performance corresponding to the ROC curve point demonstrating equal sensitivity and specificity; CI (95): 95% confidence interval of sensitivity and specificity estimates.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.

TABLE 1 Signif. Sens- TargetPS Symbol FDR D.val 5 FC Spec CI (95) 203256_at CDH3 3.75E−31 4.2476 37.54 98.3 95.5-99.5 200660_at S100A11:LOC730558:LOC730278: 2.68E−27 3.8969 3.83 97.4 93.9-99.1 LOC729659 201341_at ENC1 1.44E−26 3.667 3.93 96.7 92.6-98.7 212063_at MAPK10:CD44 3.35E−26 3.7161 7.06 96.8 92.9-98.8 217523_at MAPK10:CD44 3.35E−26 3.7151 7.06 96.8 92.9-98.8 201563_at SORD 3.44E−25 3.4659 4.36 95.8 91.3-98.3 202431_s_at LOC731404:LOC729194:MYC 5.19E−25 3.6014 4.11 96.4 92.2-98.6 221577_x_at GDF15 5.51E−25 3.5554 5.84 96.2 91.8-98.5 204702_s_at LOC650331:NFE2L3:LOC642996 1.51E−24 3.52 4.57 96.1 91.6-98.4 203961_at NEBL 5.41E−24 3.5292 5.52 96.1 91.7-98.4 203962_s_at NEBL 5.41E−24 3.5295 5.52 96.1 91.7-98.4 201338_x_at GTF3A 1.74E−22 3.2283 2.92 94.7 89.6-97.6 215091_s_at GTF3A 1.74E−22 3.2283 2.92 94.7 89.5-97.6 207850_at CXCL2:CXCL3 5.76E−22 3.2874 7.85 95   90-97.8 222549_at CLDN1 6.10E−22 3.2561 13.09 94.8 89.7-97.7 204259_at MMP7 7.61E−22 3.2624 69.29 94.9 89.8-97.7 228754_at SLC6A6:LOC728721 1.15E−21 3.2282 5.02 94.7 89.5-97.6 209774_x_at CXCL2:CXCL3 1.88E−21 3.2884 7.85 95   90-97.8 218872_at TESC 3.26E−21 3.2134 16.84 94.6 89.5-97.6 212942_s_at KIAA1199 8.12E−21 3.0489 25.16 93.6 88-97 209369_at ANXA3 1.15E−20 3.0417 3.34 93.6   87.9-97 204404_at SLC12A2 1.40E−20 3.0281 3.42 93.5 87.9-96.9 225835_at SLC12A2 1.40E−20 3.0261 3.42 93.5 87.8-96.9 219911_s_at SLCO4A1 1.46E−20 3.0968 4.84 93.9 88.4-97.2 203510_at MET 1.50E−20 3.0806 3.35 93.8 88.3-97.1 202936_s_at SOX9 1.63E−20 3.0982 3.85 93.9 88.4-97.2 201416_at SOX4 2.30E−20 3.0179 2.89 93.4 87.8-96.9 201417_at SOX4 2.30E−20 3.0146 2.89 93.4 87.7-96.9 208712_at CCND1 7.06E−20 2.9082 2.85 92.7 86.7-96.4 204351_at S100P 4.56E−19 2.9463 4.37 93 87.1-96.6 227475_at FOXQ1 4.85E−19 2.9494 10.97 93 87.1-96.6 205983_at DPEP1 5.27E−19 2.8878 23.9 92.6 86.6-96.3 204470_at CXCL2:CXCL1 5.53E−19 2.9257 10.4 92.8 86.8-96.5 212531_at LCN2 5.68E−19 2.9407 14.6 92.9   87-96.5 217867_x_at BACE2 5.87E−19 2.9042 3.8 92.7 86.7-96.4 228915_at DACH1 1.05E−18 2.9218 5.81 92.8 86.9-96.5 218704_at RNF43 2.12E−18 2.9218 3.24 92.8 86.9-96.5 202504_at TRIM29 2.36E−18 2.8231 11.01 92.1 85.9-96   241031_at NLF1 3.12E−18 2.7999 8.12 91.9 85.6-95.9 201195_s_at SLC7A5:LAT1-3TM 5.11E−18 2.7562 6.31 91.6 85.2-95.7 201656_at ITGA6 7.38E−18 2.6842 2.62 91 84.5-95.3 229215_at ASCL2 7.76E−18 2.7573 7.73 91.6 85.3-95.7 217996_at PHLDA1 1.34E−17 2.7007 5.27 91.2 84.6-95.4 205476_at CCL20 2.03E−17 2.6222 10.14 90.5 83.8-94.9 226360_at ZNRF3 2.03E−17 2.7245 4.91 91.3 84.9-95.6 219956_at GALNT6:ELA1 2.90E−17 2.682 5.27 91 84.4-95.3 201506_at TGFBI 4.14E−17 2.6863 4.31 91 84.5-95.3 212070_at GPR56 7.45E−17 2.5866 2.6 90.2 83.5-94.7 212281_s_at LOC731966:LOC729599:TMEM97 1.88E−16 2.583 2.77 90.2 83.4-94.7 202831_at GPX2 4.00E−16 2.397 3.56 88.5 81.2-93.5 225541_at LOC442108:RPL22L1 4.37E−16 2.5983 4.19 90.3 83.5-94.8 218984_at PUS7:LOC730279 5.26E−16 2.6006 3.06 90.3 83.6-94.8 219630_at PDZK1IP1 5.38E−16 2.506 4.22 89.5 82.5-94.2 202935_s_at FLJ37644 1.04E−15 2.4727 3.64 89.2 82.1-94   204401_at KCNN4 1.85E−15 2.4677 3.07 89.1 82-94 222696_at AXIN2 1.90E−15 2.4301 4.44 88.8 81.6-93.7 221923_s_at NPM1 2.22E−15 2.6018 2.18 90.3 83.5-94.8 201666_at TIMP1 2.44E−15 2.4295 3.01 88.8 81.6-93.7 210511_s_at INHBA 2.80E−15 2.5137 3.76 89.6 82.6-94.3 223062_s_at LOC651255:PSAT1:LOC389173: 3.32E−15 2.4895 5.52 89.3 82.3-94.1 LOC729779:C8orf62 225520_at MTHFD1L 4.46E−15 2.4846 4.04 89.3 82.3-94.1 206224_at CST1 7.04E−15 2.4174 13.01 88.7 81.5-93.6 201014_s_at PAICS 1.19E−14 2.3935 2.49 88.4 81.3-93.5 209309_at AZGP1:LOC401393 1.31E−14 2.3949 6.19 88.4 81.2-93.5 218796_at C20orf42 1.38E−14 2.4561 2.78 89   82-93.9 60474_at C20orf42 1.38E−14 2.4547 2.78 89 81.9-93.9 219787_s_at ECT2 1.42E−14 2.4283 2.82 88.8 81.6-93.7 231832_at WDR51B:GALNT4 1.79E−14 2.4259 2.12 88.7 81.6-93.7 218507_at HIG2 2.50E−14 2.3654 4.25 88.2 80.9-93.3 202286_s_at TACSTD2 3.13E−14 2.3701 15.71 88.2 80.9-93.3 205513_at TCN1 4.81E−14 2.3019 15.22 87.5 80.1-92.8 224428_s_at CDCA7:LOC442172 6.41E−14 2.2662 4.27 87.1 79.6-92.5 203124_s_at SLC11A2 7.07E−14 2.3616 2.18 88.1 80.8-93.3 224915_x_at TALDO1:C20orf199 8.45E−14 2.2732 2.87 87.2 79.7-92.6 226227_x_at TALDO1:C20orf199 8.45E−14 2.2707 2.87 87.2 79.7-92.6 226835_s_at TALDO1:C20orf199 8.45E−14 2.2746 2.87 87.2 79.7-92.6 200832_s_at SCD:LOC651109:LOC645313 1.23E−13 2.2759 4.28 87.2 79.8-92.6 204170_s_at CKS2 2.13E−13 2.2413 4.15 86.9 79.3-92.3 219682_s_at TBX3 3.27E−13 2.2498 4.94 87 79.4-92.4 203313_s_at TGIF 3.35E−13 2.175 2.12 86.2 78.4-91.8 201601_x_at IFITM1 4.78E−13 2.0659 3.87 84.9   77-90.8 214022_s_at IFITM1 4.78E−13 2.065 3.87 84.9   77-90.8 201328_at ETS2 5.23E−13 2.2182 2.36 86.6   79-92.2 201112_s_at CSE1L 7.98E−13 2.2336 2.28 86.8 79.2-92.2 210766_s_at CSE1L 7.98E−13 2.232 2.28 86.8 79.2-92.2 205361_s_at TMEM23:PFDN4:HDAC9 1.69E−12 2.2328 2.24 86.8 79.2-92.3 218086_at NPDC1 2.66E−12 2.169 2.53 86.1 78.4-91.8 206286_s_at TDGF1:TDGF3 3.07E−12 2.1205 6.33 85.5 77.7-91.4 204855_at SERPINB5 4.80E−12 2.1265 10.36 85.6 77.8-91.4 203878_s_at MMP11 6.30E−12 2.0959 4.55 85.3 77.4-91.1 202833_s_at SERPINA1 7.12E−12 2.0804 3.43 85.1 77.1-91   211429_s_at SERPINA1 7.12E−12 2.0818 3.43 85.1 77.2-91   228303_at No Symbol 9.19E−12 2.1527 1.61 85.9 78.2-91.6 225767_at No Symbol 9.19E−12 2.1514 1.61 85.9 78.1-91.6 226311_at No Symbol 9.19E−12 2.1527 1.61 85.9 78.1-91.6 226777_at No Symbol 9.19E−12 2.152 1.61 85.9 78.1-91.6 227140_at No Symbol 9.19E−12 2.152 1.61 85.9 78.1-91.6 229802_at No Symbol 9.19E−12 2.1519 1.61 85.9 78.2-91.6 232151_at No Symbol 9.19E−12 2.1534 1.61 85.9 78.1-91.6 213880_at LGR5 1.10E−11 2.0619 7.89 84.9 76.9-90.8 225295_at SLC39A10 2.32E−11 2.1227 1.93 85.6 77.7-91.3 205470_s_at KLK11 3.11E−11 2.0097 6.04 84.3 76.2-90.3 205174_s_at QPCT 3.46E−11 2.0435 3.03 84.7 76.6-90.7 222449_at TMEPAI 3.73E−11 2.0605 2.2 84.9   77-90.8 222450_at TMEPAI 3.73E−11 2.0616 2.2 84.9 76.9-90.9 238021_s_at LOC643911 3.73E−11 1.647 1.33 79.5 70.8-86.5 227174_at WDR72 5.22E−11 1.9844 14.11 83.9 75.8-90.1 202779_s_at UBE2S:LOC731049, UBE2S:LOC731049 5.62E−11 1.9821 2.4 83.9 75.8-90   219727_at DUOX2 9.34E−11 1.9355 9.27 83.3 75.1-89.6 210445_at FABP6 1.28E−10 1.9366 3.01 83.4 75.1-89.6 205828_at MMP3 1.44E−10 1.8964 15.63 82.8 74.6-89.2 218963_s_at KRT23 3.58E−10 1.8856 6.81 82.7 74.5-89.1 223447_at REG4 5.97E−10 1.8052 7.75 81.7 73.2-88.3 238984_at REG4 5.97E−10 1.8036 7.75 81.6 73.3-88.3 204475_at MMP1 1.22E−09 1.8132 10.59 81.8 73.4-88.3 228653_at RP5-875H10.1 1.33E−09 1.8788 1.99 82.6 74.3-89.1 204580_at MMP12 1.99E−09 1.7881 6.24 81.4   73-88.1 203895_at PLCB4 2.29E−09 1.8389 2.37 82.1 73.7-88.6 203896_s_at PLCB4 2.29E−09 1.8414 2.37 82.1 73.8-88.6 235210_s_at RPESP 2.38E−09 1.8005 9.07 81.6 73.2-88.2 201468_s_at NQO1 2.68E−09 1.6978 2.62 80.2 71.6-87.1 210519_s_at NQO1 2.68E−09 1.6973 2.62 80.2 71.6-87   222608_s_at ANLN 4.94E−09 1.7543 2.63 81 72.5-87.7 212344_at SULF1 9.70E−09 1.7754 1.74 81.3 72.9-88   212353_at SULF1 9.70E−09 1.7777 1.74 81.3 72.9-88   212354_at SULF1 9.70E−09 1.7751 1.74 81.3 72.8-87.9 201925_s_at CD55 1.45E−08 1.7612 2.22 81.1 72.6-87.8 201926_s_at CD55 1.45E−08 1.7603 2.22 81.1 72.5-87.8 202954_at PAK3:UBE2C 1.74E−08 1.6455 2.82 79.5 70.9-86.4 209792_s_at KLK10 2.64E−08 1.6142 4.52 79 70.2-86.1 205890_s_at UBD:GABBR1, UBD 4.07E−08 1.6362 6.59 79.3 70.6-86.3 209773_s_at RRM2 4.25E−08 1.6077 2.25 78.9 70.2-86   234331_s_at FAM84A:LOC653602 5.97E−08 1.6031 1.73 78.9 70.1-86   206976_s_at HSPH1 6.17E−08 1.6476 1.85 79.5 70.8-86.5 202718_at IGFBP2 8.07E−08 1.6348 1.93 79.3 70.6-86.3 225664_at TMEM30A:COL12A1 9.48E−08 1.6379 3.16 79.4 70.7-86.3 231766_s_at TMEM30A:COL12A1 9.48E−08 1.6394 3.16 79.4 70.7-86.3 201261_x_at BGN 1.01E−07 1.5939 2.69 78.7 69.9-85.9 213905_x_at BGN 1.01E−07 1.596 2.69 78.8 69.9-85.8 204127_at RFC3 1.25E−07 1.5497 2.25 78.1 69.2-85.3 207457_s_at C6orf21:LY6G6D, C6orf21:LY6G6D, 1.34E−07 1.5549 6.64 78.2 69.3-85.4 C6orf21:LY6G6D 210052_s_at TPX2 1.56E−07 1.6655 2.03 79.8 71.1-86.7 202859_x_at LOC652128:IGHG1:IGHM:IGHV4- 1.99E−07 1.6331 3.1 79.3 70.6-86.3 31:LOC647189:IGHV1- 69:IGHA1:IL8:EXOC7:SIX6:IGHD: IGH@:IGHG3:C12orf32: ZCWPW2:IFI6:IGHG4:IGHA2: IGHG2:RAC1 211506_s_at LOC652128:IGHG1:IGHM:IGHV4- 1.99E−07 1.6324 3.1 79.3 70.6-86.4 31:LOC647189:IGHV1- 69:IGHA1:IL8:EXOC7:SIX6:IGHD: IGH@:IGHG3:C12orf32: ZCWPW2:IFI6:IGHG4:IGHA2: IGHG2:RAC1 205479_s_at PLAU 2.25E−07 1.5392 3.5 77.9 69.1-85.1 238017_at RDHE2 2.71E−07 1.5511 2.52 78.1 69.3-85.3 204320_at COL11A1 2.93E−07 1.5718 2.6 78.4 69.6-85.6 37892_at COL11A1 2.93E−07 1.57 2.6 78.4 69.5-85.6 203213_at CDC2 3.58E−07 1.5342 2.72 77.8   69-85.1 210559_s_at CDC2 3.58E−07 1.5348 2.72 77.9   69-85.1 232252_at DUSP27 4.68E−07 1.5123 4.81 77.5 68.7-84.8 225799_at MGC4677, MGC4677:LOC541471 7.40E−07 1.4933 2.04 77.2 68.3-84.6 206239_s_at SPINK1 1.70E−06 1.4816 2.74 77.1 68.1-84.5 225806_at C14orf94 2.40E−06 1.6542 1.19 79.6 70.9-86.5 204885_s_at MSLN 3.78E−06 1.4263 1.93 76.2 67.2-83.7 202998_s_at ENTPD4:LOXL2 4.81E−06 1.3717 2.19 75.4 66.3-83   207158_at APOBEC1 9.49E−06 1.3811 1.63 75.5 66.4-83.1 218211_s_at MLPH 1.16E−05 1.4176 1.47 76.1 67.1-83.6 205366_s_at HOXB6 1.33E−05 1.3346 1.87 74.8 65.7-82.5 225681_at CTHRC1 1.83E−05 1.2913 2.57 74.1 64.9-81.8 205815_at REG3A 2.22E−05 1.2228 12.09 73 63.8-80.9 214974_x_at CXCL5 2.79E−05 1.281 4.48 73.9 64.8-81.7 207173_x_at CDH11 3.44E−05 1.2644 2.25 73.6 64.4-81.5 209955_s_at IFIH1:FAP 6.66E−05 1.2544 2.33 73.5 64.3-81.3 205886_at REG1B 8.08E−05 1.1731 13.15 72.1 62.8-80.1 205713_s_at COMP 0.0001 1.1543 1.69 71.8 62.6-79.9 208079_s_at AURKA:STK6P 0.0001 1.1173 1.81 71.2 61.8-79.3 209218_at SQLE 0.0001 1.1362 2.69 71.5 62.2-79.6 212190_at SERPINE2 0.0002 1.1279 1.9 71.4 62.1-79.5 219955_at L1TD1 0.0002 1.1579 2.36 71.9 62.6-79.9 236894_at L1TD1 0.0002 1.1598 2.36 71.9 62.6-79.9 209875_s_at SPP1 0.0004 1.0666 3.32 70.3 60.9-78.5 205910_s_at CEL 0.0006 1.0877 1.46 70.7 61.2-78.8 209752_at REG1A 0.0006 1.0018 10.93 69.2 59.8-77.5 213975_s_at LILRA1:LILRB1 0.0013 1.0772 1.55 70.5 61.1-78.7 202310_s_at COL1A1 0.0018 1.007 2.5 69.3 59.9-77.5 202311_s_at COL1A1 0.0018 1.0058 2.5 69.2 59.8-77.5 217430_x_at COL1A1 0.0018 1.006 2.5 69.3 59.9-77.5 221729_at COL5A2 0.0026 1.054 1.36 70.1 60.7-78.4 221730_at COL5A2 0.0026 1.0559 1.36 70.1 60.8-78.4 205825_at PCSK1 0.0029 1.107 1.48 71 61.6-79.2 203860_at PCCA 0.0038 0.9396 1.42 68.1 58.6-76.5 224646_x_at RPS12:H19 0.0051 1.0213 1.47 69.5 60.1-77.8 205941_s_at COL10A1 0.0143 0.8495 2.05 66.4   57-75.1 226237_at COL8A1 0.0254 0.8307 1.43 66.1 56.6-74.8 223970_at RETNLB 0.0304 0.8148 1.47 65.8 56.3-74.4 205765_at CYP3A5:CYP3A7 0.0545 0.8252 1.58 66 56.4-74.6 232176_at SLITRK6 0.0576 0.8693 1.31 66.8 57.3-75.4 232481_s_at SLITRK6 0.0576 0.8701 1.31 66.8 57.4-75.3 235976_at SLITRK6 0.0576 0.868 1.31 66.8 57.4-75.3 200665_s_at SPARC 0.0684 0.6727 1.45 63.2 53.6-72   205927_s_at CTSE 0.0694 0.7488 1.83 64.6 55.1-73.3 214651_s_at HOXA9 0.0759 0.7491 1.41 64.6   55-73.3 204051_s_at SFRP4 0.0829 0.6983 1.29 63.7 54.1-72.4 202404_s_at COL1A2:LOC728628 0.1891 0.6492 1.9 62.7 53.1-71.6 204620_s_at CSPG2 0.9788 0.1834 1.05 53.7 44-63 221731_x_at CSPG2 0.9788 0.183 1.05 53.6 44.1-63   203083_at THBS2 0.9844 0.2784 1.26 55.5   46-64.8 214235_at CYP3A5:CYP3A43:CYP3A5P2 0.9932 0.3165 1.16 56.3 46.7-65.6

TABLE 2 Gene Symbol ValidPS_UP CDH3 802708-HuGene_st:280037-HuGene_st:1019645-HuGene_st:119416- HuGene_st:642035-HuGene_st:665706-HuGene_st:249831- HuGene_st:604066-HuGene_st:260528-HuGene_st:166615- HuGene_st:411984-HuGene_st:520679-HuGene_st:1071177- HuGene_st:988525-HuGene_st:317603-HuGene_st:301020- HuGene_st:693824-HuGene_st:468436-HuGene_st:203256_at:265728- HuGene_st:806796-HuGene_st:893171-HuGene_st ENC1 216704-HuGene_st:529141-HuGene_st:968541-HuGene_st:1015647- HuGene_st:524348-HuGene_st:291883-HuGene_st:154485- HuGene_st:174870-HuGene_st:967480-HuGene_st:729586- HuGene_st:826381-HuGene_st:40464-HuGene_st:340065- HuGene_st:1066975-HuGene_st:1090631-HuGene_st:201340_s_at:86039- HuGene_st:686829-HuGene_st:733896-HuGene_st:201341_at:698873- HuGene_st:730768-HuGene_st:403595-HuGene_st CD44 366106-HuGene_st:314808-HuGene_st:59730-HuGene_st:599371- HuGene_st:391296-HuGene_st:1031797-HuGene_st:314340- HuGene_st:10723-HuGene_st:950067-HuGene_st:282016- HuGene_st:480680-HuGene_st:69560-HuGene_st:388781- HuGene_st:243049-HuGene_st:374652-HuGene_st:194553- HuGene_st:1075454-HuGene_st:204489_s_at:619139- HuGene_st:210916_s_at:542762- HuGene_st:1557905_s_at:212014_x_at:229221_at:204490_s_at:234418_x_at: 209835_x_at:212063_at:216062_at:777408- HuGene_st:234411_x_at:217523_at:216056_at:1565868_at:83114- HuGene_st SORD 510024-HuGene_st:895709-HuGene_st:1079720-HuGene_st:566899- HuGene_st:339498-HuGene_st:91263-HuGene_st:256497- HuGene_st:720484-HuGene_st:187420-HuGene_st:580807- HuGene_st:267000-HuGene_st:321981-HuGene_st:1019581- HuGene_st:1020801-HuGene_st:520376-HuGene_st:670131- HuGene_st:201562_s_at:455746-HuGene_st:67454- HuGene_st:201563_at:309303-HuGene_st:1001165-HuGene_st:411387- HuGene_st:49636-HuGene_st MYC 292645-HuGene_st:257928-HuGene_st:284020-HuGene_st:517374- HuGene_st:869576-HuGene_st:1099727-HuGene_st:33994- HuGene_st:781657-HuGene_st:509634-HuGene_st:273419- HuGene_st:1068468-HuGene_st:1095763-HuGene_st:149150- HuGene_st:841622-HuGene_st:730300-HuGene_st:964312- HuGene_st:963427-HuGene_st:202431_s_at:522112- HuGene_st:244089_at:239931_at:649622-HuGene_st GDF15 716715-HuGene_st:81268-HuGene_st:221576_at:1032661- HuGene_st:430762-HuGene_st:392223-HuGene_st:325978- HuGene_st:273598-HuGene_st:229868_s_at:835644-HuGene_st:271704- HuGene_st:1097896-HuGene_st:692830-HuGene_st:1033023- HuGene_st:85522-HuGene_st:954824-HuGene_st:221577_x_at:634293- HuGene_st:594344-HuGene_st:231517-HuGene_st:307405- HuGene_st:31827-HuGene_st:496173-HuGene_st:636515- HuGene_st:30047-HuGene_st NFE2L3 95873-HuGene_st:1058969-HuGene_st:86088-HuGene_st:1093456- HuGene_st:347351-HuGene_st:878719-HuGene_st:880179- HuGene_st:240089_at:822197-HuGene_st:873612-HuGene_st:517821- HuGene_st:489354-HuGene_st:20603-HuGene_st:204702_s_at NEBL 923272-HuGene_st:580150-HuGene_st:925039-HuGene_st:451073- HuGene_st:23015-HuGene_st:714203-HuGene_st:479241- HuGene_st:1092604-HuGene_st:458919-HuGene_st:207279_s_at:932542- 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HuGene_st:204885_s_at:870302-HuGene_st:246473-HuGene_st:58043- HuGene_st:122629-HuGene_st:826602-HuGene_st:689741- HuGene_st:931732-HuGene_st:227498-HuGene_st LOXL2 818138-HuGene_st:46172-HuGene_st:346541-HuGene_st:281266- HuGene_st:202998_s_at:1074111-HuGene_st:228808_s_at:271051- HuGene_st:827532-HuGene_st:228823-HuGene_st:950166- HuGene_st:254550-HuGene_st:260752-HuGene_st:937941- HuGene_st:328673-HuGene_st:966956-HuGene_st:84360- HuGene_st:34062-HuGene_st:291104-HuGene_st:898787- HuGene_st:202997_s_at:626390-HuGene_st:929733-HuGene_st APOBEC1 735977-HuGene_st:188849-HuGene_st:423265-HuGene_st:882201- HuGene_st:237979-HuGene_st:708999-HuGene_st:293863- HuGene_st:372914-HuGene_st:237042-HuGene_st:207158_at:1080489- HuGene_st:815110-HuGene_st:417875-HuGene_st:745636- HuGene_st:34403-HuGene_st:650730-HuGene_st:164111- HuGene_st:360993-HuGene_st MLPH 549562-HuGene_st:92890-HuGene_st:305885-HuGene_st:709610- HuGene_st:337433-HuGene_st:128794-HuGene_st:824637- HuGene_st:131043-HuGene_st:702794-HuGene_st:533212- HuGene_st:398611-HuGene_st:423382-HuGene_st:865544- HuGene_st:546078-HuGene_st:505182-HuGene_st:400420- HuGene_st:316126-HuGene_st:586617-HuGene_st:506198- HuGene_st:218211_s_at:229150_at:976628-HuGene_st HOXB6 339062-HuGene_st:885612-HuGene_st:1075575-HuGene_st:746940- HuGene_st:103632-HuGene_st:883931-HuGene_st:552163- HuGene_st:249935-HuGene_st:726433-HuGene_st:31257- HuGene_st:242080-HuGene_st:630137-HuGene_st:959882- HuGene_st:546294-HuGene_st:241578-HuGene_st:142774- HuGene_st:881260-HuGene_st:290100-HuGene_st:447667- HuGene_st:205366_s_at:299629-HuGene_st:831836-HuGene_st CTHRC1 235232-HuGene_st:86783-HuGene_st:426340-HuGene_st:385407- HuGene_st:647908-HuGene_st:756615-HuGene_st:978256- HuGene_st:651961-HuGene_st:193568-HuGene_st:310105- HuGene_st:393578-HuGene_st REG3A 290546-HuGene_st:265033-HuGene_st:385905-HuGene_st:459677- HuGene_st:230871-HuGene_st:214805-HuGene_st:1060074- HuGene_st:816902-HuGene_st:1092213-HuGene_st:942177- HuGene_st:191737-HuGene_st:729928-HuGene_st:205815_at:256155- HuGene_st:677349-HuGene_st CXCL5 264137-HuGene_st:272626-HuGene_st:745715-HuGene_st:968572- HuGene_st:1054472-HuGene_st:394185-HuGene_st:181128- HuGene_st:456756-HuGene_st:415578- HuGene_st:215101_s_at:214974_x_at:935926-HuGene_st:781518- HuGene_st:235326-HuGene_st:941963-HuGene_st:242589- HuGene_st:798477-HuGene_st:257906-HuGene_st:350119- HuGene_st:222708-HuGene_st CDH11 167614-HuGene_st:234040-HuGene_st:609892-HuGene_st:583244- HuGene_st:863670-HuGene_st:599824-HuGene_st:142981- HuGene_st:96018-HuGene_st:217538-HuGene_st:634855- HuGene_st:60296-HuGene_st:546348-HuGene_st:206371- HuGene_st:960949-HuGene_st:353648-HuGene_st:184349- HuGene_st:356919-HuGene_st:611963-HuGene_st:626011- HuGene_st:543798-HuGene_st:207173_x_at:207172_s_at FAP 993707-HuGene_st:132558-HuGene_st:581008- HuGene_st:209955_s_at:600137-HuGene_st:284881-HuGene_st:40379- HuGene_st REG1B 796972-HuGene_st:1089426-HuGene_st:762519-HuGene_st:270006- HuGene_st:553619-HuGene_st:279169-HuGene_st:342759- HuGene_st:337497-HuGene_st:898145-HuGene_st:603979- HuGene_st:134214-HuGene_st:469380-HuGene_st:332107- HuGene_st:608771-HuGene_st:965588-HuGene_st:205886_at:1010838- HuGene_st:714363-HuGene_st:29068-HuGene_st:215693-HuGene_st COMP 401785-HuGene_st:710767-HuGene_st:996888-HuGene_st:348725- HuGene_st:492440-HuGene_st:307171-HuGene_st:121009- HuGene_st:205713_s_at AURKA 147919-HuGene_st:826493-HuGene_st:453415-HuGene_st:126529- HuGene_st:799451-HuGene_st:673418-HuGene_st:571370- HuGne_st:470643-HuGene_st:926370-HuGene_st:93908- HuGene_st:426906-HuGene_st:636365-HuGene_st:326617- HuGene_st:208080_at:582788-HuGene_st:647783-HuGene_st:458308- HuGene_st:204092_s_at:121857-HuGene_st:1059753-HuGene_st:70315- HuGene_st SQLE 181699-HuGene_st:213577_at:285928-HuGene_st:367103- HuGene_st:827097-HuGene_st:213562_s_at:819545-HuGene_st:354972- HuGene_st:779168-HuGene_st:1010566-HuGene_st:47822- HuGene_st:861626-HuGene_st:895693-HuGene_st:94812- HuGene_st:967759-HuGene_st:625566-HuGene_st:890030- HuGene_st:566347-HuGene_st:296617-HuGene_st:894379- HuGene_st:1023221-HuGene_st:198540-HuGene_st:117280-HuGene_st L1TD1 859419-HuGene_st:968483-HuGene_st:1010927- HuGene_st:236894_at:715579-HuGene_st:540230-HuGene_st:414266- HuGene_st:572495-HuGene_st:327643-HuGene_st:1058922- HuGene_st:18534-HuGene_st:1063550-HuGene_st:1030986- HuGene_st:842123-HuGene_st:709222-HuGene_st:887612- HuGene_st:219955_at:496121-HuGene_st:942986-HuGene_st:799837- HuGene_st SERPINE2 443903-HuGene_st:959444-HuGene_st:48734-HuGene_st:664848- HuGene_st:1052179-HuGene_st:227487_s_at:902213-HuGene_st:621638- HuGene_st:230208-HuGene_st:14188-HuGene_st:854259- HuGene_st:929830-HuGene_st:670835-HuGene_st:48860- HuGene_st:31861-HuGene_st:722385-HuGene_st:1057158- HuGene_st:466703-HuGene_st:10961-HuGene_st:824130- HuGene_st:347407-HuGene_st:205406-HuGene_st CEL 1553970_s_at:898561-HuGene_st:857424-HuGene_st:456577- HuGene_st:1035054-HuGene_st:539061-HuGene_st:788693- HuGene_st:314198-HuGene_st:786044-HuGene_st:205910_s_at:958725- HuGene_st:473620-HuGene_st:74757-HuGene_st:169727- HuGene_st:711091-HuGene_st:461956-HuGene_st:897116- HuGene_st:911062-HuGene_st:796522-HuGene_st LILRB1 213975_s_at COL1A1 487433-HuGene_st:719132- HuGene_st:1556499_s_at:202311_s_at:202310_s_at:1003153- HuGene_st:1029566-HuGene_st COL5A2 292241-HuGene_st PCSK1 981596-HuGene_st:31911-HuGene_st:701212-HuGene_st:673651- HuGene_st:166044-HuGene_st:989024-HuGene_st:1039153- HuGene_st:688811-HuGene_st:1068709-HuGene_st:1083910- HuGene_st:527047-HuGene_st:994213-HuGene_st:190818- HuGene_st:785459-HuGene_st:127562-HuGene_st:1012339- HuGene_st:343010-HuGene_st:109185-HuGene_st:115345- HuGene_st:470044-HuGene_st:856975-HuGene_st:454100-HuGene_st PCCA 54827-HuGene_st:1042448-HuGene_st:175778-HuGene_st:203860_at H19 634871-HuGene_st:51379-HuGene_st:803516-HuGene_st:336451- HuGene_st:254511-HuGene_st:632993-HuGene_st COL10A1 288876-HuGene_st:815716-HuGene_st:615071-HuGene_st:865385- HuGene_st:1067078-HuGene_st CYP3A5 NA CYP3A5P2 NA SLITRK6 NA SPARC NA CTSE NA HOXA9 NA SFRP4 NA COL1A2 NA THBS2 NA Gene Signif. Sens- CI Symbol Symbol FDR D.val 5 FC Spec (95) CDH3 CDH3 3.75E−31 4.2474 37.54 98.3 95.5-99.5 ENC1 ENC1 1.44E−26 3.6666 3.93 96.7 92.6-98.7 CD44 MAPK10: 3.35E−26 3.7114 7.06 96.8 92.9-98.8 CD44 SORD SORD 3.44E−25 3.4665 4.36 95.8 91.3-98.3 MYC LOC731404: 5.19E−25 3.5977 4.11 96.4 92.2-98.6 LOC729194: MYC GDF15 GDF15 5.51E−25 3.5534 5.84 96.2 91.9-98.5 NFE2L3 LOC650331: 1.51E−24 3.523 4.57 96.1 91.7-98.4 NFE2L3: LOC642996 NEBL NEBL 5.41E−24 3.5322 5.52 96.1 91.7-98.4 GTF3A GTF3A 1.74E−22 3.2254 2.92 94.7 89.5-97.6 CLDN1 CLDN1 6.10E−22 3.2528 13.09 94.8 89.7-97.7 MMP7 MMP7 7.61E−22 3.2633 69.29 94.9 89.8-97.7 SLC6A6 SLC6A6: 1.15E−21 3.2313 5.02 94.7 89.6-97.6 LOC728721 CXCL1 CXCL2: 1.88E−21 3.2911 7.85 95   90-97.8 CXCL3 CXCL2 CXCL2: 1.95E−21 3.2941 7.85 95   90-97.8 CXCL3 CXCL3 CXCL2: 1.95E−21 3.2892 7.85 95 90.1-97.8 CXCL3 TESC TESC 3.26E−21 3.2128 16.84 94.6 89.4-97.6 KIAA1199 KIAA1199 8.12E−21 3.0498 25.16 93.6 88-97 ANXA3 ANXA3 1.15E−20 3.0459 3.34 93.6 88-97 SLCO4A1 SLCO4A1 1.46E−20 3.0952 4.84 93.9 88.4-97.2 MET MET 1.50E−20 3.0827 3.35 93.8 88.3-97.1 SOX9 SOX9 1.63E−20 3.0954 3.85 93.9 88.4-97.2 SOX4 SOX4 2.30E−20 3.0197 2.89 93.4 87.7-96.9 CCND1 CCND1 7.06E−20 2.9073 2.85 92.7 86.8-96.4 FOXQ1 FOXQ1 4.85E−19 2.9444 10.97 93 87.1-96.6 DPEP1 DPEP1 5.27E−19 2.8897 23.9 92.6 86.5-96.3 LCN2 LCN2 5.68E−19 2.9407 14.6 92.9   87-96.6 BACE2 BACE2 5.87E−19 2.9056 3.8 92.7 86.7-96.4 DACH1 DACH1 1.05E−18 2.9243 5.81 92.8 86.8-96.5 RNF43 RNF43 2.12E−18 2.9237 3.24 92.8 86.9-96.5 TRIM29 TRIM29 2.36E−18 2.8229 11.01 92.1 85.9-96   NLF1 NLF1 3.12E−18 2.7997 8.12 91.9 85.7-95.9 SLC7A5 SLC7A5: 5.11E−18 2.7527 6.31 91.6 85.2-95.7 LAT1- 3TM ASCL2 ASCL2 7.76E−18 2.7559 7.73 91.6 85.3-95.7 PHLDA1 PHLDA1 1.34E−17 2.701 5.27 91.2 84.7-95.4 CCL20 CCL20 2.03E−17 2.6209 10.14 90.5 83.8-94.9 ZNRF3 ZNRF3 2.03E−17 2.7278 4.91 91.4 84.9-95.5 TMEM97 LOC731966: 1.88E−16 2.5821 2.77 90.2 83.4-94.7 LOC729599: TMEM97 GPX2 GPX2 4.00E−16 2.3996 3.56 88.5 81.2-93.5 RPL22L1 LOC442108: 4.37E−16 2.6007 4.19 90.3 83.6-94.9 RPL22L1 PUS7 PUS7:LOC730279 5.26E−16 2.6017 3.06 90.3 83.6-94.8 PDZK1IP1 PDZK1IP1 5.38E−16 2.5049 4.22 89.5 82.5-94.2 FLJ37644 FLJ37644 1.04E−15 2.4695 3.64 89.2 82.1-94   KCNN4 KCNN4 1.85E−15 2.4698 3.07 89.2 82.1-94   AXIN2 AXIN2 1.90E−15 2.4309 4.44 88.8 81.7-93.7 NPM1 NPM1 2.22E−15 2.6004 2.18 90.3 83.6-94.8 TIMP1 TIMP1 2.44E−15 2.4307 3.01 88.8 81.6-93.7 INHBA INHBA 2.80E−15 2.5141 3.76 89.6 82.7-94.3 PSAT1 LOC651255: 3.32E−15 2.4893 5.52 89.3 82.3-94.2 PSAT1: LOC389173: LOC729779:C8orf62 MTHFD1L MTHFD1L 4.46E−15 2.4849 4.04 89.3 82.3-94.1 CST1 CST1 7.04E−15 2.4183 13.01 88.7 81.6-93.7 PAICS PAICS 1.19E−14 2.3937 2.49 88.4 81.2-93.5 AZGP1 AZGP1: 1.31E−14 2.3989 6.19 88.5 81.3-93.5 LOC401393 C20orf42 C20orf42 1.38E−14 2.4573 2.78 89   82-93.9 ECT2 ECT2 1.42E−14 2.4271 2.82 88.8 81.6-93.7 WDR51B WDR51B: 1.79E−14 2.4266 2.12 88.7 81.6-93.7 GALNT4 HIG2 HIG2 2.50E−14 2.366 4.25 88.2 80.9-93.3 TACSTD2 TACSTD2 3.13E−14 2.3686 15.71 88.2 80.9-93.3 TCN1 TCN1 4.81E−14 2.3035 15.22 87.5   80-92.8 CDCA7 CDCA7: 6.41E−14 2.2638 4.27 87.1 79.6-92.5 LOC442172 SLC11A2 SLC11A2 7.07E−14 2.362 2.18 88.1 80.7-93.2 SCD SCD:LOC651109: 1.23E−13 2.2789 4.28 87.3 79.8-92.6 LOC645313 CKS2 CKS2 2.13E−13 2.2406 4.15 86.9 79.2-92.3 TBX3 TBX3 3.27E−13 2.249 4.94 87 79.5-92.4 CSE1L CSE1L 7.98E−13 2.2314 2.28 86.8 79.2-92.3 PFDN4 TMEM23: 1.69E−12 2.2333 2.24 86.8 79.1-92.3 PFDN4: HDAC9 NPDC1 NPDC1 2.66E−12 2.1699 2.53 86.1 78.3-91.7 TDGF1 TDGF1: 3.07E−12 2.1179 6.33 85.5 77.7-91.3 TDGF3 IL8 AHNAK: 3.28E−12 2.3281 1.73 87.8 80.3-93   IGHG1 SERPINB5 SERPINB5 4.80E−12 2.1258 10.36 85.6 77.8-91.4 MMP11 MMP11 6.30E−12 2.0946 4.55 85.3 77.4-91.1 SERPINA1 SERPINA1 7.12E−12 2.0812 3.43 85.1 77.1-91   LGR5 LGR5 1.10E−11 2.0623 7.89 84.9 76.9-90.8 KLK11 KLK11 3.11E−11 2.0091 6.04 84.2 76.1-90.4 QPCT QPCT 3.46E−11 2.0418 3.03 84.6 76.6-90.6 TMEPAI TMEPAI 3.73E−11 2.0603 2.2 84.9 76.9-90.8 WDR72 WDR72 5.22E−11 1.9862 14.11 84 75.8-90.1 UBE2S UBE2S: 5.62E−11 1.9793 2.4 83.9 75.8-90.1 LOC731049, UBE2S: LOC731049 DUOX2 DUOX2 9.34E−11 1.9359 9.27 83.3 75.1-89.6 FABP6 FABP6 1.28E−10 1.9367 3.01 83.4 75.2-89.6 MMP3 MMP3 1.44E−10 1.8957 15.63 82.8 74.5-89.2 KRT23 KRT23 3.58E−10 1.887 6.81 82.7 74.4-89.1 MMP1 MMP1 1.22E−09 1.8163 10.59 81.8 73.5-88.4 RP5- RP5- 1.33E−09 1.8807 1.99 82.6 74.4-89.1 875H10.1 875H10.1 MMP12 MMP12 1.99E−09 1.7858 6.24 81.4 73-88 PLCB4 PLCB4 2.29E−09 1.8407 2.37 82.1 73.8-88.6 RPESP RPESP 2.38E−09 1.8014 9.07 81.6 73.1-88.2 ANLN ANLN 4.94E−09 1.7558 2.63 81 72.5-87.7 SULF1 SULF1 9.70E−09 1.7762 1.74 81.3 72.8-87.9 CD55 CD55 1.45E−08 1.7603 2.22 81.1 72.6-87.8 UBE2C PAK3:UBE2C 1.74E−08 1.6437 2.82 79.4 70.8-86.5 KLK10 KLK10 2.64E−08 1.6155 4.52 79 70.3-86.1 UBD UBD:GABBR1, 4.07E−08 1.6371 6.59 79.3 70.5-86.3 UBD RRM2 RRM2 4.25E−08 1.608 2.25 78.9 70.2-86   FAM84A FAM84A: 5.97E−08 1.6052 1.73 78.9 70-86 LOC653602 HSPH1 HSPH1 6.17E−08 1.647 1.85 79.5 70.8-86.5 IGFBP2 IGFBP2 8.07E−08 1.6359 1.93 79.3 70.6-86.3 COL12A1 TMEM30A: 9.48E−08 1.6377 3.16 79.4 70.7-86.3 COL12A1 BGN BGN 1.01E−07 1.594 2.69 78.7   70-85.8 RFC3 RFC3 1.25E−07 1.551 2.25 78.1 69.2-85.3 LY6G6D C6orf21: 1.34E−07 1.5536 6.64 78.1 69.3-85.4 LY6G6D, C6orf21: LY6G6D, C6orf21:LY6G6D TPX2 TPX2 1.56E−07 1.6664 2.03 79.8 71.1-86.7 PLAU PLAU 2.25E−07 1.5372 3.5 77.9 69.1-85.2 RDHE2 RDHE2 2.71E−07 1.5509 2.52 78.1 69.2-85.3 COL11A1 COL11A1 2.93E−07 1.5722 2.6 78.4 69.6-85.5 CDC2 CDC2 3.58E−07 1.5339 2.72 77.8   69-85.1 DUSP27 DUSP27 4.68E−07 1.5106 4.81 77.5 68.6-84.8 LOC541471 MGC4677, 7.40E−07 1.4932 2.04 77.2 68.3-84.6 MGC4677:LOC541471 SPINK1 SPINK1 1.70E−06 1.4805 2.74 77 68.1-84.4 C14orf94 C14orf94 2.40E−06 1.653 1.19 79.6 70.8-86.5 MSLN MSLN 3.78E−06 1.4279 1.93 76.2 67.2-83.8 LOXL2 ENTPD4: 4.81E−06 1.373 2.19 75.4 66.3-82.9 LOXL2 APOBEC1 APOBEC1 9.49E−06 1.3847 1.63 75.6 66.5-83.1 MLPH MLPH 1.16E−05 1.4174 1.47 76.1 67.1-83.6 HOXB6 HOXB6 1.33E−05 1.3346 1.87 74.8 65.6-82.4 CTHRC1 CTHRC1 1.83E−05 1.2895 2.57 74 64.9-81.8 REG3A REG3A 2.22E−05 1.2218 12.09 72.9 63.7-80.8 CXCL5 CXCL5 2.79E−05 1.2805 4.48 73.9 64.8-81.7 CDH11 CDH11 3.44E−05 1.2652 2.25 73.7 64.4-81.5 FAP IFIH1:FAP 6.66E−05 1.2541 2.33 73.5 64.2-81.3 REG1B REG1B 8.08E−05 1.1728 13.15 72.1 62.8-80.1 COMP COMP 0.0001 1.1565 1.69 71.8 62.6-79.9 AURKA AURKA: 0.0001 1.1173 1.81 71.2 61.8-79.3 STK6P SQLE SQLE 0.0001 1.1354 2.69 71.5 62.1-79.6 L1TD1 L1TD1 0.0002 1.1589 2.36 71.9 62.6-79.9 SERPINE2 SERPINE2 0.0002 1.1283 1.9 71.4 62.1-79.4 CEL CEL 0.0006 1.0863 1.46 70.6 61.3-78.8 LILRB1 LILRA1: 0.0013 1.0781 1.55 70.5 61.1-78.7 LILRB1 COL1A1 COL1A1 0.0018 1.0063 2.5 69.3 59.9-77.6 COL5A2 COL5A2 0.0026 1.0556 1.36 70.1 60.8-78.3 PCSK1 PCSK1 0.0029 1.1077 1.48 71 61.7-79.1 PCCA PCCA 0.0038 0.939 1.42 68.1 58.6-76.5 H19 RPS12: 0.0051 1.0228 1.47 69.5 60.2-77.8 H19 COL10A1 COL10A1 0.0143 0.8493 2.05 66.4  6.9-74.9 CYP3A5 CYP3A5: 0.0562 0.8249 1.58 66 56.5-74.6 CYP3A7 CYP3A5P2 CYP3A5: 0.0562 0.8246 1.58 66 56.5-74.6 CYP3A7 SLITRK6 SLITRK6 0.0576 0.8687 1.31 66.8 57.3-75.3 SPARC SPARC 0.0684 0.6714 1.45 63.1 53.6-72   CTSE CTSE 0.0694 0.7465 1.83 64.6   55-73.3 HOXA9 HOXA9 0.0759 0.7505 1.41 64.6 55.1-73.3 SFRP4 SFRP4 0.0829 0.6983 1.29 63.7   54-72.4 COL1A2 COL1A2: 0.1891 0.6508 1.9 62.8 53.1-71.6 LOC728628 THBS2 THBS2 0.9844 0.2782 1.26 55.5 45.9-64.8

TABLE 3 Signif. Sens- TargetPS Symbol FDR D.val5 FC Spec CI (95) 217523_at MAPK10:CD44 3.35E−26 3.7166 7.06 96.8 92.9-98.8 204702_s_at LOC650331:NFE2L3:LOC642996 1.51E−24 3.521 4.57 96.1 91.7-98.4 207850_at CXCL2:CXCL3 5.76E−22 3.2893 7.85 95   90-97.8 204259_at MMP7 7.61E−22 3.2634 69.29 94.9 89.8-97.7 228915_at DACH1 1.05E−18 2.9232 5.81 92.8 86.9-96.5 241031_at NLF1 3.12E−18 2.8001 8.12 91.9 85.7-95.9 223062_s_at LOC651255:PSAT1:LOC389173:LOC729779: 3.32E−15 2.4882 5.52 89.3 82.3-94.2 C8orf62 206224_at CST1 7.04E−15 2.4165 13.01 88.7 81.5-93.6 209309_at AZGP1:LOC401393 1.31E−14 2.3986 6.19 88.5 81.3-93.5 219787_s_at ECT2 1.42E−14 2.4245 2.82 88.7 81.6-93.7 202286_s_at TACSTD2 3.13E−14 2.3676 15.71 88.2 80.9-93.3 227140_at No Symbol 9.19E−12 2.1522 1.61 85.9 78.2-91.6 229802_at No Symbol 9.19E−12 2.1536 1.61 85.9 78.2-91.6 213880_at LGR5 1.10E−11 2.0621 7.89 84.9 76.9-90.8 205174_s_at QPCT 3.46E−11 2.0422 3.03 84.6 76.7-90.6 238021_s_at LOC643911 3.73E−11 1.6459 1.33 79.5 70.8-86.5 227174_at WDR72 5.22E−11 1.9854 14.11 84 75.8-90.1 238984_at REG4 5.97E−10 1.8033 7.75 81.6 73.2-88.3 204475_at MMP1 1.22E−09 1.8138 10.59 81.8 73.4-88.4 222608_s_at ANLN 4.94E−09 1.7541 2.63 81 72.4-87.7 211506_s_at LOC652128:IGHG1:IGHM:IGHV4- 1.99E−07 1.6343 3.1 79.3 70.6-86.3 31:LOC647189:IGHV1- 69:IGHA1:IL8:EXOC7:SIX6:IGHD: IGH@:IGHG3:C12orf32:ZCWPW2: IFI6:IGHG4:IGHA2:IGHG2:RAC1 204320_at COL11A1 2.93E−07 1.5718 2.6 78.4 69.6-85.6 37892_at COL11A1 2.93E−07 1.5707 2.6 78.4 69.6-85.6 232252_at DUSP27 4.68E−07 1.5112 4.81 77.5 68.6-84.8 225806_at C14orf94 2.40E−06 1.6519 1.19 79.6 70.9-86.6 204885_s_at MSLN 3.78E−06 1.4266 1.93 76.2 67.2-83.7 214974_x_at CXCL5 2.79E−05 1.2818 4.48 73.9 64.7-81.6 236894_at L1TD1 0.0002 1.1596 2.36 71.9 62.6-79.9 205910_s_at CEL 0.0006 1.0869 1.46 70.7 61.3-78.8 202311_s_at COL1A1 0.0018 1.0054 2.5 69.2 59.9-77.6 205825_at PCSK1 0.0029 1.1086 1.48 71 61.7-79.1 226237_at COL8A1 0.0254 0.8303 1.43 66.1 56.6-74.7 235976_at SLITRK6 0.0576 0.8689 1.31 66.8 57.2-75.3

TABLE 4 Gene Symbol ValidPS_UP Symbol Signif. FDR D. val5 FC Sens-Spec CI (95) CD44 356106-HuGene_st:314808-HuGene_st:59730- MAPK10:CD44 3.35E−26 3.7136 7.06 96.8 92.9-98.8 HuGene_st:599371-HuGene_st:391296- HuGene_st:1031797-HuGene_st:314340- HuGene_st:10723-HuGene_st:950067- HuGene_st:282016-HuGene_st:480680- HuGene_st:69560-HuGene_st:388781- HuGene_st:243049-HuGene_st:374652- HuGene_st:194553-HuGene_st:1075454- HuGene_st:204489_s_at:619139- HuGene_st:210916_s_at:542762- HuGene_st:1557905_s_at:212014_x_at:229221_(—) at:204490_s_at:234418_x_at:209835_x_at:212063_at:216062_at:777408- HuGene_st:234411_x_at:217523_at:216056_at:1565868_at:83114- HuGene_st NFE2L3 95873-HuGene_st:1058969-HuGene_st:86088- LOC650331:NFE2L3:LOC642996 1.51E−24 3.5213 4.57 96.1 91.6-98.4 HuGene_st:1093456-HuGene_st:347351- HuGene_st:8798719-HuGene_st:880179- HuGene_st:240089_at:822197- HuGene_st:873612-HuGene_st:517821- HuGene_st:489354-HuGene_st:20603- HuGene_st:204702_s_at MMP7 267137-HuGene_st:1068392- MMP7 7.61E−22 3.2652 69.29 94.9 89.8-97.8 HuGene_st:794865-HuGene_st:876922- HuGene_st:669567-HuGene_st:1039935- HuGene_st:514120-HuGene_st:1092830- HuGene_st:745768-HuGene_st:272260- HuGene_st:30733-HuGene_st:401681- HuGene_st:854024-HuGene_st:221616- HuGene_st:805045-HuGene_st:783838- HuGene_st:204259_at:934756- HuGene_st:446688-HuGene_st:10259- HuGene_st:267021-HuGene_st:889042- HuGene_st CXCL3 11327-HuGene_st:626337-HuGene_st:322604- CXCL2:CXCL3 1.95E−21 3.2907 7.85 95  90-97.8 HuGene_st:256806-HuGene_st:261067- HuGene_st:448247-HuGene_st:666569- HuGene_st:222646-HuGene_st:262117- HuGene_st:798675-HuGene_st:391369- HuGene_st:865299-HuGene_st:877897- HuGene_st:575433-HuGene_st:43120- HuGene_st:42070-HuGene_st:33632- HuGene_st:965957-HuGene_st:556939- HuGene_st:26460-HuGene_st:796450- HuGene_st:230101_at:541868- HuGene_st:490134-HuGene_st:1064107- HuGene_st:230192-HuGene_st:645829- HuGene_st:455502-HuGene_st:249140- HuGene_st:906606-HuGene_st:1098767- HuGene_st:721989-HuGene_st:500578- HuGene_st:33301- HuGene_st:207850_at:622384- HuGene_st:209774_x_at:432036- HuGene_st:30559-HuGene_st:187557- HuGene_st:1101027-HuGene_st:1038334- HuGene_st:260925-HuGene_st:515662- HuGene_st:258081- HuGene_st:1569203_at:280828- HuGene_st:1000069-HuGene_st:509822- HuGene_st:890213-HuGene_st:739461- HuGene_st:342746-HuGene_st:98929- HuGene_st:818131-HuGene_st:1091592- HuGene_st:420504-HuGene_st:41644- HuGene_st:655278-HuGene_st:188562- HuGene_st:458602-HuGene_st DACH1 686187-HuGene_st:985190- DACH1 1.05E−18 2.9206 5.81 92.8 86.9-96.5 HuGene_st:1011822-HuGene_st:1092705- HuGene_st:693255-HuGene_st:722787- HuGene_st:465556-HuGene_st:113230- HuGene_st:49101-HuGene_st:290879- HuGene_st:646013-HuGene_st:3984- HuGene_st:378631-HuGene_st:1002554- HuGene_st:620749-HuGene_st:802309- HuGene_st:82679- HuGene_st:205471_s_at:303920- HuGene_st:338273-HuGene_st:20454- HuGene_st:1567100_at:205472_s_at:228915_(—) at:1562342_at:169641-HuGene_st:984254- HuGene_st:1567101_at NLF1 269939-HuGene_st:314919- NLF1 3.12E−18 2.8001 8.12 91.9 85.7-95.9 HuGene_st:552234-HuGene_st:622058- HuGene_st:68900-HuGene_st:376228- HuGene_st:194806-HuGene_st:923707- HuGene_st:745661-HuGene_st:996995- HuGene_st:534469-HuGene_st:560627- HuGene_st:711203- HuGene_st:241031_at:93378- HuGene_st:611899-HuGene_st:57671- HuGene_st:443570-HuGene_st:231416- HuGene_st PSAT1 139416-HuGene_st:795030- LOC651255:PSAT1:LOC389173:LOC729779:C8orf62 3.32E−15 2.4883 5.52 89.3 82.3-94.1 HuGene_st:160439-HuGene_st:322148- HuGene_st:85375-HuGene_st:223335- HuGene_st:2658-HuGene_st:399855- HuGene_st:220892_s_at:941491- HuGene_st:1017348-HuGene_st:856207- HuGene_st:194347-HuGene_st:553133- HuGene_st:223062_s_at:987517- HuGene_st:336174-HuGene_st CST1 95123-HuGene_st:125297-HuGene_st:235257- CST1 7.04E−15 2.4165 13.01 88.7 81.5-93.7 HuGene_st:102028-HuGene_st:291462- HuGene_st:206224_at:906914- HuGene_st:936009-HuGene_st:1055285- HuGene_st AZGP1 363333-HuGene_st:620891- AZGPI:LOC401393 1.31E−14 2.3984 6.19 88.5 81.3-93.5 HuGene_st:619378-HuGene_st:741747- HuGene_st:28018-HuGene_st:594026- HuGene_st:222884-HuGene_st:1006522- HuGene_st:974237-HuGene_st:473891- HuGene_st:784628-HuGene_st:488818- HuGene_st:209309_at:217014_s_at:63620- HuGene_st:366096-HuGene_st:950952- HuGene_st:601798-HuGene_st:399823- HuGene_st:734365-HuGene_st:1054227- HuGene_st ECT2 770888-HuGene_st:82454-HuGene_st:171418- ECT2 1.42E−14 2.4269 2.82 88.8 81.6-93.7 HuGene_st:52318-HuGene_st:530079- HuGene_st:288145- HuGene_st:234992_x_at:64803- HuGene_st:705846-HuGene_st:158155- HuGene_st:554622- HuGene_st:237241_at:629949- HuGene_st:222681-HuGene_st:241642- HuGene_st:143403-HuGene_st:770445- HuGene_st:218688-HuGene_st:700408- HuGene_st:165018-HuGene_st:917458- HuGene_st:219787_s_at:609829- HuGene_st:110350-HuGene_st TACSTD2 1004611-HuGene_st:755233- TACSTD2 3.13E−14 2.3693 15.71 88.2 80.9-93.3 HuGene_st:815649-HuGene_st:567105- HuGene_st:8281-HuGene_st:1041491- HuGene_st:339450- HuGene_st:227128_s_at:653539- HuGene_st:1079680-HuGene_st:958592- HuGene_st:202286_s_at:620831- HuGene_st:53075-HuGene_st:1009541- HuGene_st:861600-HuGene_st:181597- HuGene_st:130895-HuGene_st:849592- HuGene_st IL8 1044664-HuGene_st:714746- AHNAK:IGHG1 3.28E−12 2.3273 1.73 87.8 80.3-93  HuGene_st:442029-HuGene_st:119200- HuGene_st:550444-HuGene_st:493978- HuGene_st:713906-HuGene_st:943156- HuGene_st:504843-HuGene_st:501902- HuGene_st:497219-HuGene_st:23149- HuGene_st:387164-HuGene_st:562654- HuGene_st:1047492-HuGene_st:538558- HuGene_st:239300- HuGene_st:211430_s_at:390695- HuGene_st:1081759-HuGene_st:144630- HuGene_st:661013-HuGene_st:393191- HuGene_st:55017-HuGene_st:1005159- HuGene_st:359116-HuGene_st:373132- HuGene_st:689050-HuGene_st:611041- HuGene_st:715689-HuGene_st:289354- HuGene_st:820633-HuGene_st:555788- HuGene_st:988945-HuGene_st:307991- HuGene_st:211506_s_at:924368- HuGene_st:47911-HuGene_st:929972- HuGene_st:561100-HuGene_st:68522- HuGene_st:217039_x_at:231668_x_at:1080400- HuGene_st:141662-HuGene_st:765200- HuGene_st:648539-HuGene_st:274868- HuGene_st:233969_at LGR5 784585-HuGene_st:777519- LGR5 1.10E−11 2.0645 7.89 84.9 76.9-90.8 HuGene_st:937559-HuGene_st:297045- HuGene_st:796093-HuGene_st:783411- HuGene_st:876648-HuGene_st:842003- HuGene_st:102017-HuGene_st:562251- HuGene_st:295997-HuGene_st:747520- HuGene_st:811121-HuGene_st:677407- HuGene_st:522834-HuGene_st:475414- HuGene_st:802999-HuGene_st:1066925- HuGene_st:216864-HuGene_st:890928- HuGene_st:179502-HuGene_st:79633- HuGene_st:210393_at:241266_at:213880_at QPCT 261837-HuGene_st:108729- QPCT 3.46E−11 2.0415 3.03 84.6 76.7-90.6 HuGene_st:942514-HuGene_st:184578- HuGene_st:454020-HuGene_st:202482- HuGene_st:1012784-HuGene_st:854999- HuGene_st:62841-HuGene_st:271540- HuGene_st:524919-HuGene_st:78507- HuGene_st:89785-HuGene_st:728309- HuGene_st:625205-HuGene_st:170279- HuGene_st:561083-HuGene_st:322236- HuGene_st:205174_s_at:303448-HuGene_st WDR72 829740-HuGene_st:1063796- WDR72 5.22E−11 1.9856 14.11 84 75.9-90  HuGene_st:725768- HuGene_st:227174_at:36564- HuGene_st:236741_at:604794- HuGene_st:1040675-HuGene_st:527199- HuGene_st:1052168- HuGene_st:1563874_at:77868- HuGene_st:667158-HuGene_st:542462- HuGene_st:136243-HuGene_st:551835- HuGene_st REG4 186424-HuGene_st:382639- REG4 5.97E−10 1.8057 7.75 81.7 73.3-88.3 HuGene_st:931162-HuGene_st:400261- HuGene_st:638045-HuGene_st:852602- HuGene_st:628254-HuGene_st:849775- HuGene_st:274371- HuGene_st:1554436_a_at:1092015- HuGene_st:223447_at:29614- HuGene_st:661518-HuGene_st:580789- HuGene_st:929866-HuGene_st:160171- HuGene_st:954850-HuGene_st:758344- HuGene_st:254891- HuGene_st:238984_at:421464- HuGene_st:758547-HuGene_st:364821- HuGene_st:701510-HuGene_st MMP1 61706-HuGene_st:300572- MMP1 1.22E−09 1.8141 10.59 81.8 73.4-88.4 HuGene_st:1020786-HuGene_st:437171- HuGene_st:671620-HuGene_st:689073- HuGene_st:622653-HuGene_st:958445- HuGene_st:445730-HuGene_st:914223- HuGene_st:693724-HuGene_st:673683- HuGene_st:524115-HuGene_st:422476- HuGene_st:361198-HuGene_st:710307- HuGene_st:468477-HuGene_st:840324- HuGene_st:1070117-HuGene_st:473664- HuGene_st:732367- HuGene_st:204475_at:353235-HuGene_st ANLN 522941-HuGene_st:550252- ANLN 4.94E−09 1.7566 2.63 81 72.5-87.7 HuGene_st:477118-HuGene_st:858635- HuGene_st:34728-HuGene_st:165560- HuGene_st:226318-HuGene_st:207100- HuGene_st:842538-HuGene_st:343961- HuGene_st:899690-HuGene_st:705871- HuGene_st:42619-HuGene_st:984996- HuGene_st:733290-HuGene_st:1008901- HuGene_st:752472-HuGene_st:619756- HuGene_st:674545-HuGene_st:558324- HuGene_st:261208- HuGene_st:222608_s_at:1552619_a_at COL11A1 254341-HuGene_st:485975- COL11A1 2.93E−07 1.5724 2.6 78.4 69.6-85.6 HuGene_st:869898-HuGene_st:755872- HuGene_st:2674-HuGene_st:230890- HuGene_st:6042-HuGene_st:1100922- HuGene_st:800510-HuGene_st:64257- HuGene_st:301971-HuGene_st:360139- HuGene_st:549979-HuGene_st:603002- HuGene_st:756718-HuGene_st:1043994- HuGene_st:198973-HuGene_st:550144- HuGene_st:986684-HuGene_st:743059- HuGene_st:708360-HuGene_st:575064- HuGene_st:633985-HuGene_st:392228- HuGene_st:204320_at:121425- HuGene_st:468885-HuGene_st:20543- HuGene_st:170503-HuGene_st DUSP27 612025-HuGene_st:737703- DUSP27 4.68E−07 1.5098 4.81 77.5 68.6-84.8 HuGene_st:124098-HuGene_st:102948- HuGene_st:35826-HuGene_st:226732- HuGene_st:513585-HuGene_st:135885- HuGene_st:737040-HuGene_st:446627- HuGene_st:724445-HuGene_st:289189- HuGene_st:5396-HuGene_st:520095- HuGene_st:172210-HuGene_st:277848- HuGene_st:312172-HuGene_st:903613- HuGene_st:232252_at:303717- HuGene_st:846174-HuGene_st C14orf94 225806_at:243446_at:88782- C14orf94 2.40E−06 1.6524 1.19 79.6 70.9-86.5 HuGene_st:537586-HuGene_st:973643- HuGene_st:646464-HuGene_st:729584- HuGene_st:973338-HuGene_st:95576- HuGene_st:301260-HuGene_st:559586- HuGene_st:942952-HuGene_st:82798- HuGene_st:218383_at:165751- HuGene_st:965936-HuGene_st:31043- HuGene_st:650638-HuGene_st:984201- HuGene_st:925802-HuGene_st:306659- HuGene_st:345230-HuGene_st MSLN 63302-HuGene_st:821643-HuGene_st:99135- MSLN 3.78E−06 1.427 1.93 76.2 67.2-83.7 HuGene_st:192667-HuGene_st:765000- HuGene_st:44188-HuGene_st:59621- HuGene_st-465236-HuGene_st:559922- HuGene_st:82252-HuGene_st:1039687- HuGene_st:1053735- HuGene_st:204885_s_at:870302- HuGene_st:246473-HuGene_st:58043- HuGene_st:122629-HuGene_st:826602- HuGene_st:689741-HuGene_st:931732- HuGene_st:227498-HuGene_st CXCL5 264137-HuGene_st:272626- CXCL5 2.79E−05 1.2814 4.48 73.9 64.7-81.7 HuGene_st:745715-HuGene_st:968572- HuGene_st:1054472-HuGene_st:394185- HuGene_st:181128-HuGene_st:456756- HuGene_st:415578- HuGene_st:215101_s_at:214974_x_at:935926- HuGene_st:781518-HuGene_st:235326- HuGene_st:941963-HuGene_st:242589- HuGene_st:798477-HuGene_st:257906- HuGene_st:350119-HuGene_st:222708- HuGene_st L1TD1 859419-HuGene_st:968483- L1TD1 2.00E−04 1.1595 2.36 71.9 62.6-79.9 HuGene_st:1010927- HuGene_st:236894_at:715579- HuGene_st:540230-HuGene_st:414266- HuGene_st:572495-HuGene_st:327643- HuGene_st:1058922-HuGene_st:18534- HuGene_st:1063550-HuGene_st:1030986- HuGene_st:842123-HuGene_st:709222- HuGene_st:887612- HuGene_st:219955_at:496121- HuGene_st:942986-HuGene_st:799837- HuGene_st CEL 1553970_s_at:898561-HuGene_st:857424- CEL 6.00E−04 1.0872 1.46 70.7 61.3-78.8 HuGene_st:456577-HuGene_st:1035054- HuGene_st:539061-HuGene_st:788693- HuGene_st:314198-HuGene_st:786044- HuGene_st:205910_s_at:958725- HuGene_st:473620-HuGene_st:74757- HuGene_st:169727-HuGene_st:711091- HuGene_st:461956-HuGene_st:897116- HuGene_st:911062-HuGene_st:796522- HuGene_st COL1A1 487433-HuGene_st:719132- COL1A1 1.80E−03 1.0053 2.5 69.2 59.9-77.6 HuGene_st:1556499_s_at:202311_s_at:202310_(—) s_at:1003153-HuGene_st:1029566-HuGene_st PCSK1 981596-HuGene_st:31911-HuGene_st:701212- PCSK1 2.90E−03 1.1082 1.48 71 61.6-79.1 HuGene_st:673651-HuGene_st:166044- HuGene_st:989024-HuGene_st:1039153- HuGene_st:688811-HuGene_st:1068709- HuGene_st:1083910-HuGene_st:527047- HuGene_st:994213-HuGene_st:190818- HuGene_st:785459-HuGene_st:127562- HuGene_st:1012339-HuGene_st:343010- HuGene_st:109185-HuGene_st:115345- HuGene_st:470044-HuGene_st:856975- HuGene_st:454100-HuGene_st COL8A1 713455-HuGene_st COL8A1 2.54E−02 0.8325 1.43 66.1 56.6-74.7

TABLE 5 TargetPS Symbol Signif. FDR D. val5 FC Sens-Spec CI (95) 213106_at ATP8A1 6.60E−08 2.2884 3.11 87.4 76.9-94.1 210107_at CLCA1 3.19E−07 2.1573 9.98 86 75.2-93.1 204811_s_at CACNA2D2 3.61E−05 1.659 4.41 79.7 67.7-88.5 223969_s_at RETNLB 4.3968E−05  1.6581 11.64 79.6 67.7-88.5 223970_at RETNLB 4.3968E−05  1.6576 11.64 79.6 67.8-88.5 228232_s_at VSIG2 0.0001 1.5718 2.4 78.4 66.3-87.6 242601_at LOC253012 0.0001 1.5777 5.28 78.5 66.5-87.6 227719_at No Symbol 0.0002 1.642 1.98 79.4 67.4-88.3 237521_x_at No Symbol 0.0002 1.6433 1.98 79.4 67.5-88.3 203240_at FCGBP 3.00E−04 1.5005 3.07 77.3 65.2-86.7 204897_at PTGER4 6.00E−04 1.4732 1.55 76.9 64.7-86.4 227676_at FAM3D 0.001  1.2706 2.15 73.7 61.3-83.8 205765_at CYP3A5 1.20E−03 1.5279 1.8 77.8 65.6-87.1 232176_at SLITRK6 0.0016 1.3618 5.96 75.2 62.8-85  232481_s_at SLITRK6 0.0016 1.3607 5.96 75.2 62.9-85  235976_at SLITRK6 0.0016 1.3648 5.96 75.3 62.9-84.9 221874_at KIAA1324 3.80E−03 1.325 2.1 74.6 62.2-84.5 226248_s_at KIAA1324 0.0038 1.3246 2.1 74.6 62.2-84.6 204607_at HMGCS2 5.20E−03 1.2354 3.59 73.2 60.7-83.3 203963_at CA12 6.50E−03 1.1828 1.86 72.3 59.7-82.6 204508_s_at CA12 6.50E−03 1.1861 1.86 72.3 59.8-82.6 215867_x_at CA12 6.50E−03 1.1858 1.86 72.3 59.7-82.6 227725_at ST6GALNAC1 0.0068 1.1419 1.76 71.6 59-82 200884_at CKB 7.30E−03 1.1481 2.25 71.7 59.1-82.1 219955_at L1TD1 7.70E−03 1.2502 3.27 73.4 60.9-83.5 236894_at L1TD1 0.0077 1.2465 3.27 73.3 60.9-83.5 205259_at NR3C2 1.29E−02 1.1933 1.63 72.5 60.1-82.8 218211_s_at MLPH 1.38E−02 1.2269 1.59 73 60.5-83.2 214234_s_at CYP3A5P2 1.94E−02 1.098 1.7 70.8 58.1-81.3 214235_at CYP3A5P2 1.94E−02 1.0976 1.7 70.8 58.2-81.3 204895_x_at MUC4:TAF5L:LOC650855:LOC645744 4.53E−02 1.1998 1.31 72.6 60.1-82.8 217109_at MUC4:TAF5L:LOC650855:LOC645744 4.53E−02 1.2028 1.31 72.6 60.2-82.8 217110_s_at MUC4:TAF5L:LOC650855:LOC645744 4.53E−02 1.198 1.31 72.5  60-82.8 221841_s_at KLF4 7.31E−02 1.0009 1.58 69.2 56.5-79.9 215125_s_at UGT1A9 7.37E−02 1.0664 1.28 70.3 57.6-80.9 208063_s_at CAPN9 7.40E−02 0.998 1.84 69.1 56.4-79.9 214433_s_at SELENBP1 9.02E−02 0.9783 2 68.8  56-79.6 226302_at ATP8B1 0.093  1.039 1.4 69.8 57.2-80.5 231832_at WDR51B 0.1284 1.0008 1.28 69.2 56.5-79.9 219543_at PBLD 1.66E−01 0.8734 1.89 66.9 54.2-77.9 208937_s_at ID1 2.34E−01 0.7639 1.66 64.9 52.1-76.2 205927_s_at CTSE 2.81E−01 0.7393 3.23 64.4 51.6-75.8 229070_at C6orf105 0.7794 0.7027 1.37 63.7 50.9-75.2

TABLE 6 TargetPS Symbol Signif. FDR D. val5 FC Sens-Spec CI (95) 200665_s_at SPARC  3.05E−09 2.3771 3.24 88.3  78-94.6 212667_at SPARC 3.0479E−09 2.3752 3.24 88.3 78.1-94.6 211964_at COL4A2 5.5315E−09 2.4316 2.87 88.8 78.8-95  211966_at COL4A2 5.5315E−09 2.4321 2.87 88.8 78.8-95  211980_at COL4A1  1.243E−08 2.3031 3.03 87.5 77.2-94.2 211981_at COL4A1  1.243E−08 2.3045 3.03 87.5 77.2-94.2 218638_s_at SPON2 1.9471E−08 2.3321 3.38 87.8 77.5-94.3 221729_at COL5A2 5.7658E−08 2.2145 3.31 86.6  76-93.5 221730_at COL5A2 5.7658E−08 2.2138 3.31 86.6 75.9-93.6 208782_at FSTL1 7.8434E−08 2.228 2.64 86.7 76.1-93.7 201261_x_at BGN 9.6881E−08 2.2253 2.99 86.7  76-93.6 213905_x_at BGN 9.6881E−08 2.2232 2.99 86.7 76.1-93.6 209955_s_at IFIH1:FAP  1.358E−07 2.2261 4.88 86.7 76.2-93.6 226237_at COL8A1 3.6053E−07 2.1456 3.09 85.8 75-93 202310_s_at COL1A1  5.44E−07 2.0121 3.29 84.3 73-92 202311_s_at COL1A1  5.44E−07 2.0131 3.29 84.3 73.1-92  217430_x_at COL1A1 5.4426E−07 2.015 3.29 84.3 73.2-92  201438_at COL6A3 5.7026E−07 2.0286 2.73 84.5 73.5-92.1 202403_s_at COL1A2:LOC728628  8.85E−07 2.0609 2.62 84.9 73.9-92.4 202404_s_at COL1A2:LOC728628  8.85E−07 2.0621 2.62 84.9 73.7-92.4 229218_at COL1A2:LOC728628 8.8466E−07 2.0618 2.62 84.9 73.9-92.4 208850_s_at THY1 1.0326E−06 1.9159 3.34 83.1 71.8-91.1 208851_s_at THY1 1.0326E−06 1.915 3.34 83.1 71.7-91.1 213869_x_at THY1 1.0326E−06 1.9132 3.34 83.1 71.7-91.1 203477_at COL15A1 1.0611E−06 2.0121 3.37 84.3 73.2-91.9 201616_s_at CALD1  1.11E−06 2.1136 1.7 85.5 74.6-92.8 212077_at CALD1 1.1059E−06 2.1131 1.7 85.5 74.5-92.8 201162_at IGFBP7 1.1574E−06 2.0016 1.91 84.2 72.9-91.8 201163_s_at IGFBP7  1.16E−06 1.999 1.91 84.1  73-91.9 210511_s_at INHBA 1.1943E−06 2.0027 3.38 84.2  73-91.9 225664_at TMEM30A:COL12A1 1.2492E−06 2.0313 4.16 84.5 73.4-92.1 231766_s_at TMEM30A:COL12A1 1.2492E−06 2.0303 4.16 84.5 73.4-92.1 231879_at TMEM30A:COL12A1 1.2492E−06 2.0325 4.16 84.5 73.5-92.1 203325_s_at COL5A1 1.6076E−06 1.934 2.75 83.3 72.1-91.3 212488_at COL5A1 1.6076E−06 1.9342 2.75 83.3 72.1-91.3 212489_at COL5A1 1.6076E−06 1.9339 2.75 83.3  72-91.2 203083_at THBS2 2.3382E−06 1.9081 6.5 83 71.6-91  202291_s_at MGP:C12orf46  2.50E−06 1.9993 2.62 84.1  73-91.9 201645_at TNC  3.74E−06 1.9608 2.14 83.7 72.5-91.5 201852_x_at COL3A1  9.29E−06 1.8472 2.32 82.2 70.7-90.5 211161_s_at COL3A1 9.2906E−06 1.8501 2.32 82.3 70.7-90.5 215076_s_at COL3A1 9.2906E−06 1.8495 2.32 82.2 70.7-90.5 232458_at COL3A1 9.2906E−06 1.8473 2.32 82.2 70.7-90.5 212344_at SULF1 1.4436E−05 1.7528 2.84 81 69.3-89.5 212353_at SULF1 1.4436E−05 1.7555 2.84 81 69.2-89.5 212354_at SULF1 1.4436E−05 1.7521 2.84 80.9 69.3-89.5 201185_at HTRA1 1.7178E−05 1.7346 2.29 80.7 68.9-89.3 202998_s_at ENTPD4:LOXL2  1.99E−05 1.7754 2.45 81.3 69.6-89.7 224724_at SULF2 2.0766E−05 1.6837 2.25 80 68.2-88.7 233555_s_at SULF2 2.0766E−05 1.6795 2.25 79.9  68-88.7 201069_at MMP2 2.5409E−05 1.7345 3.02 80.7  69-89.3 201147_s_at TIMP3  2.62E−05 1.7776 2.56 81.3 69.6-89.7 201150_s_at TIMP3  2.62E−05 1.7774 2.56 81.3 69.6-89.7 209156_s_at COL6A2 2.9551E−05 1.7373 1.67 80.7  69-89.4 227099_s_at LOC387763   0.00003052 1.8968 1.43 82.9 71.4-90.9 214247_s_at DKK3 3.1838E−05 1.7434 1.86 80.8 69.1-89.5 202450_s_at CTSK  3.98E−05 1.7153 2.16 80.4 68.7-89.1 225799_at MGC4677, MGC4677:LOC541471 4.1139E−05 1.8003 1.45 81.6 70-90 209395_at CHI3L1:MYBPH 5.1515E−05 1.6358 3.06 79.3 67.4-88.2 209396_s_at CHI3L1:MYBPH 5.1515E−05 1.6352 3.06 79.3 67.4-88.2 202878_s_at CD93  5.19E−05 1.6674 2.36 79.8 67.9-88.6 204320_at COL11A1 5.3391E−05 1.7594 2.55 81 69.3-89.6 37892_at COL11A1 5.3391E−05 1.7556 2.55 81 69.3-89.6 221011_s_at LBH 6.3299E−05 1.6771 1.9 79.9 68.1-88.7 213125_at OLFML2B 6.6557E−05 1.7057 1.97 80.3 68.5-89  204475_at MMP1 7.0616E−05 1.6759 3.91 79.9  68-88.8 226694_at AKAP2:PALM2:PALM2-AKAP2 7.4206E−05 1.7231 1.58 80.6 68.8-89.2 202766_s_at FBN1 0.0001 1.5984 1.48 78.8 66.7-87.9 205828_at MMP3 0.0001 1.6223 6.68 79.1 67.3-88.1 207191_s_at ISLR 0.0001 1.6448 1.87 79.5 67.5-88.4 213428_s_at COL6A1 0.0001 1.7301 1.58 80.6 68.8-89.3 226930_at FNDC1 0.0001 1.521 3.14 77.7 65.6-87  201792_at AEBP1 0.0002 1.4772 2.11 77 64.8-86.5 203878_s_at MMP11 0.0002 1.6971 1.28 80.2 68.4-88.9 211959_at IGFBP5 0.0002 1.5662 3.96 78.3 66.3-87.5 225710_at No Symbol 0.0002 1.6426 1.98 79.4 67.5-88.4 226311_at No Symbol 0.0002 1.6436 1.98 79.4 67.5-88.3 226777_at No Symbol 0.0002 1.645 1.98 79.5 67.5-88.4 227140_at No Symbol 0.0002 1.6427 1.98 79.4 67.6-88.3 229802_at No Symbol 0.0002 1.6421 1.98 79.4 67.5-88.3 205479_s_at PLAU 0.0003 1.484 2.11 77.1 64.9-86.5 210495_x_at FN1 0.0003 1.494 2.87 77.2 65.1-86.6 211719_x_at FN1 0.0003 1.4894 2.87 77.2 65.1-86.7 212464_s_at FN1 0.0003 1.493 2.87 77.2  65-86.7 216442_x_at FN1 0.0003 1.4935 2.87 77.2  65-86.6 217762_s_at RAB31 0.0003 1.4864 2.08 77.1  65-86.6 217763_s_at RAB31 0.0003 1.4848 2.08 77.1 64.9-86.6 217764_s_at RAB31 0.0003 1.4882 2.08 77.2  65-86.5 225681_at CTHRC1 0.0003 1.4588 3.41 76.7 64.5-86.3 201105_at LGALS1 0.0004 1.4844 1.61 77.1 64.9-86.6 208788_at ELOVL5 0.0004 1.5418 1.86 78 65.8-87.2 224694_at ANTXR1 0.0005 1.52 2 77.6 65.5-86.9 200974_at ACTA2 0.0006 1.4251 1.75 76.2  64-85.8 210095_s_at IGFBP3 0.0006 1.5538 1.38 78.1  66-87.4 201426_s_at VIM  8.00E−04 1.4819 1.48 77.1 64.9-86.4 219087_at ASPN 0.0009 1.4046 2.75 75.9 63.6-85.5 227566_at HNT 0.001  1.4215 2.26 76.1  64-85.7 201667_at GJA1  1.30E−03 1.4084 1.63 75.9 63.7-85.6 200600_at MSN  1.40E−03 1.4942 1.36 77.2  65-86.7 204051_s_at SFRP4 0.0015 1.4056 2.2 75.9 63.6-85.6 209101_at CTGF 0.0015 1.3331 1.78 74.7 62.4-84.6 204620_s_at CSPG2 0.0016 1.21 1.38 72.7 60.3-83  211571_s_at CSPG2 0.0016 1.2123 1.38 72.8 60.1-82.9 215646_s_at CSPG2 0.0016 1.2095 1.38 72.7 60.3-83  221731_x_at CSPG2 0.0016 1.2115 1.38 72.8 60.3-83  204006_s_at FCGR3B 0.0026 1.2308 2.14 73.1 60.6-83.2 203570_at LOXL1 0.0027 1.4048 1.33 75.9 63.7-85.6 201744_s_at LUM  2.90E−03 1.3418 2.18 74.9 62.5-84.7 202283_at SERPINF1  3.10E−03 1.2121 1.76 72.8 60.2-83  209596_at MXRA5 0.0034 1.2974 1.62 74.2 61.7-84.1 210809_s_at POSTN 0.005  1.3011 2.58 74.2 61.8-84.2 205547_s_at TAGLN 0.0051 1.1829 2.19 72.3 59.7-82.6 202237_at NNMT  5.40E−03 1.223 1.44 73 60.4-83.1 202238_s_at NNMT  5.40E−03 1.2259 1.44 73 60.5-83.1 218468_s_at GREM1 0.007  1.3017 1.31 74.2 61.8-84.2 218469_at GREM1 0.007  1.3027 1.31 74.3 61.9-84.2 208747_s_at C1S 0.0088 1.3575 1.77 75.1 62.9-85  224560_at TIMP2 0.0097 1.1629 1.72 72 59.4-82.3 231579_s_at TIMP2 0.0097 1.1641 1.72 72 59.5-82.4 209875_s_at SPP1 0.0109 1.0673 3.91 70.3 57.6-80.9 202859_x_at IL8 0.0112 1.3238 4.54 74.6 62.2-84.5 200832_s_at SCD:LOC651109:LOC645313  1.27E−02 1.0749 2.33 70.5 57.9-81.1 201058_s_at MYL9 0.0131 1.1765 1.37 72.2 59.6-82.5 203645_s_at CD163 0.0146 1.1655 2.19 72 59.4-82.3 215049_x_at CD163 0.0146 1.1664 2.19 72 59.4-82.3 202917_s_at S100A8  1.48E−02 1.0979 3.17 70.8 58.3-81.4 201289_at CYR61 0.015  1.0919 1.69 70.7 58.1-81.2 210764_s_at CYR61 0.015  1.0938 1.69 70.8 58.2-81.2 218559_s_at MAFB 0.0182 1.162 1.48 71.9 59.3-82.3 203382_s_at APOE 0.0285 1.1124 1.43 71.1 58.5-81.6 201893_x_at DCN  3.64E−02 1.0821 1.29 70.6  58-81.1 211813_x_at DCN 0.0364 1.0838 1.29 70.6 57.8-81.1 211896_s_at DCN 0.0364 1.0814 1.29 70.6  58-81.1 213524_s_at G0S2 0.0383 0.994 1.53 69 56.3-79.8 207173_x_at CDH11 0.0384 1.0121 1.98 69.4 56.6-80.1 209218_at SQLE 0.041  1.0162 2.15 69.4 56.6-80.1 201141_at GPNMB 0.0623 1.0165 1.52 69.4 56.7-80.1 201859_at PRG1 0.0634 0.798 1.34 65.5 52.6-76.7 234994_at KIAA1913 0.1061 0.9579 1.2 68.4 55.7-79.3 223122_s_at SFRP2 0.1336 0.968 1.24 68.6 55.9-79.4 223235_s_at SMOC2 0.2175 0.6547 2.06 62.8  50-74.4 200986_at SERPING1 0.2636 0.7831 1.26 65.2 52.4-76.4 201842_s_at EFEMP1  4.91E−01 0.6821 1.27 63.3 50.5-74.8 204122_at TYROBP 0.4923 0.7066 1.23 63.8 51.1-75.3 202620_s_at PLOD2  5.15E−01 0.7784 1.51 65.1 52.3-76.4

TABLE 7 Gene Symbol ValidPS_UP Symbol Signif. FDR D. val5 FC Sens-Spec CI (95) ATP8A1 231484_at:792569- ATP8A1 6.60E−08 2.2854 3.11 87.3 76.9-94  HuGene_st:210192_at:393806- HuGene_st:743026-HuGene_st:200684- HuGene_st:1570592_a_at:645563- HuGene_st:245580-HuGene_st:175799- HuGene_st:20566-HuGene_st:636204- HuGene_st:376757-HuGene_st:273140- HuGene_st:873028-HuGene_st:864954- HuGene_st:349056-HuGene_st:538894- HuGene_st:167620-HuGene_st:807498- HuGene_st CLCA1 210107_at:426361-HuGene_st:389155- CLCA1 3.19E−07 2.1536 9.98 85.9 75.1-93.1 HuGene_st:622359-HuGene_st:523802- HuGene_st:196470-HuGene_st:1078884- HuGene_st:515258-HuGene_st:638133- HuGene_st:764167-HuGene_st:921948- HuGene_st:372283-HuGene_st:252084- HuGene_st:98798-HuGene_st:1059095- HuGene_st:441678-HuGene_st:490107- HuGene_st:284008-HuGene_st:258568- HuGene_st:602588-HuGene_st:472452- HuGene_st:640066-HuGene_st CACNA2D2 805306-HuGene_st:1022165- ACNA2D2 3.61E−05 1.6587 4.41 79.7 67.8-88.5 HuGene_st:356782-HuGene_st:70395- HuGene_st:525161-HuGene_st:729314- HuGene_st:866616-HuGene_st:13978- HuGene_st:715678-HuGene_st:299289- HuGene_st:592015-HuGene_st:756393- HuGene_st:607464-HuGene_st:862691- HuGene_st:229636_at:885048- HuGene_st:680228-HuGene_st:393608- HuGene_st:886897-HuGene_st:413699- HuGene_st RETNLB 173654-HuGene_st:223970_at:1094109- RETNLB 4.40E−05 1.6599 11.64 79.7 67.8-88.5 HuGene_st:708431-HuGene_st:231770- HuGenest:1065075-HuGene_st:318917- HuGene_st:719419-HuGene_st:380366- HuGene_st:221119-HuGene_st:774168- HuGene_st:223969_s_at:523432- HuGene_st:45260-HuGene_st:963420- HuGene_st:329703-HuGene_st:223761- HuGene_st:1036667-HuGene_st:143113- HuGene_st:414008-HuGene_st:232543- HuGene_st VSIG2 391438-HuGene_st:228232_s_at:265221- VSIG2 0.0001 1.5745 2.4 78.4 66.3-87.6 HuGene_st:343187-HuGene_st:223925- HuGene_st:652010-HuGene_st:1069591- HuGene_st:265186-HuGene_st:1095607- HuGene_st:788466-HuGene_st:675062- HuGene_st:826720-HuGene_st:1093892- HuGene_st:985113-HuGene_st:637781- HuGene_st:997596-HuGene_st LOC253012 1014415-HuGene_st:912640- LOC253012 0.0001 1.5764 5.28 78.5 66.5-87.7 HuGene_st:463072-HuGene_st:749900- HuGene_st:381523-HuGene_st:896826- HuGene_st:804632-HuGene_st:304834- HuGene_st:39629-HuGene_st:568837- HuGene_st:1070854-HuGene_st:162938- HuGene_st:1026726-HuGene_st:441915- HuGene_st:242601_at:51876- HuGene_st:199784-HuGene_st:363568- HuGene_st:50979-HuGene_st:736612- HuGene_st FCGBP 203240_at:88809-HuGene_st:1085208- FCGBP 0.0003 1.4997 3.07 77.3 65.2-86.7 HuGene_st:338164-HuGene_st:71797- HuGene_st:1079875-HuGene_st:63672- HuGene_st:997435-HuGene_st:226428- HuGene_st:948120-HuGene_st:22847- HuGene_st:36995-HuGene_st:508230- HuGene_st:16108-HuGene_st:311904- HuGene_st:426005-HuGene_st:27264- HuGene_st:516715-HuGene_st:841000- HuGene_st:708701-HuGene_st:781083- HuGene_st:634071-HuGene_st:948682- HuGene_st PTGER4 204896_s_at:109314-HuGene_st:986807- PTGER4 0.0006 1.4713 1.55 76.9 64.7-86.4 HuGene_st:446764-HuGene_st:548266- HuGene_st:919403-HuGene_st:965220- HuGene_st:192344-HuGene_st:1943- HuGene_st:252442-HuGene_st:392964- HuGene_st:23686- HuGene_st:204897_at:812085-HuGene_st FAM3D 361373-HuGene_st:963526- FAM3D 0.001 1.2699 2.15 73.7 61.3-83.8 HuGene_st:227676_at:741172- HuGene_st:608385-HuGene_st:1074915- HuGene_st:182670-HuGene_st:24363- HuGene_st:269456-HuGene_st:833883- HuGene_st:280625-HuGene_st:187246- HuGene_st:964986-HuGene_st:66738- HuGene_st:80884-HuGene_st CYP3A5 205765_at:67735- CYP3A5 0.0012 1.5288 1.8 77.8 65.7-87  HuGene_st:214234_s_at:941416- HuGene_st:238807-HuGene_st:611620- HuGene_st CYP3A5P2 205765_at:67735- CYP3A5 0.0012 1.5297 1.8 77.8 65.6-87  HuGene_st:214234_s_at:941416- HuGene_st:238807-HuGene_st:611620- HuGene_st SLITRK6 936650-HuGene_st:921047- SLITRK6 0.0016 1.36 5.96 75.2 62.8-85  HuGene_st:371185-HuGene_st:510939- HuGene_st:356154-HuGene_st:205559- HuGene_st:386297-HuGene_st:483895- HuGene_st:227644-HuGene_st:458058- HuGene_st:232481_s_at:907326- HuGene_st:255645-HuGene_st:830582- HuGene_st:615220-HuGene_st:369624- HuGene_st:78770-HuGene_st:573187- HuGene_st:1025122-HuGene_st:584646- HuGene_st KIAA1324 243349_at:226248_s_at:1052694- KIAA1324 0.0038 1.3258 2.1 74.6 62.2-84.5 HuGene_st:893707-HuGene_st:397814- HuGene_st:585604-HuGene_st:240530- HuGene_st HMGCS2 616916-HuGene_st:283650- HMGCS2 0.0052 1.234 3.59 73.1 60.6-83.3 HuGene_st:204607_at:43162- HuGene_st:371076-HuGene_st:407398- HuGene_st:900260-HuGene_st:619083- HuGene_st:729816-HuGene_st:171889- HuGene_st:253113-HuGene_st:448587- HuGene_st:593619-HuGene_st:624250- HuGene_st:865416-HuGene_st:888308- HuGene_st:397691-HuGene_st:789982- HuGene_st:658722-HuGene_st CA12 215867_x_at:210735_s_at:204508_s_at:203963_at:638145- CA12 0.0065 1.1823 1.86 72.3 59.7-82.6 HuGene_st:1013062-HuGene_st:280470- HuGene_st:214164_x_at:875965- HuGene_st:749017-HuGene_st:1049334- HuGene_st:439438-HuGene_st:65565- HuGene_st:1017708-HuGene_st:226479- HuGene_st:125567-HuGene_st:698714- HuGene_st:963408-HuGene_st:189118- HuGene_st:1049350-HuGene_st ST6GALNAC1 524915-HuGene_st:694442- ST6GALNAC1 0.0068 1.1407 1.76 71.6 58.9-82  HuGene_st:372293-HuGene_st:247017- HuGene_st:186959-HuGene_st:149798- HuGene_st:611157-HuGene_st:887450- HuGene_st:227725_at:608767- HuGene_st:891399-HuGene_st:95718- HuGene_st:780611-HuGene_st:1006431- HuGene_st:266448-HuGene_st:768462- HuGene_st:616368-HuGene_st:66760- HuGene_st:1067993-HuGene_st:69927- HuGene_st:104705-HuGene_st CKB 200884_at:435665-HuGene_st:888623- CKB 0.0073 1.1468 2.25 71.7 59.2-82.1 HuGene_st:480007-HuGene_st:396007- HuGene_st:963331-HuGene_st:40899- HuGene_st:373774-HuGene_st:25470- HuGene_st:16603-HuGene_st:766369- HuGene_st:405417-HuGene_st:718720- HuGene_st:1041238-HuGene_st:23457- HuGene_st:24890-HuGene_st:769422- HuGene_st:896708-HuGene_st:581051- HuGene_st:549987-HuGene_st:384128- HuGene_st L1TD1 219955_at:842123-HuGene_st:1095330- L1TD1 0.0077 1.2497 3.27 73.4 60.9-83.5 HuGene_st:1058922-HuGene_st:572495- HuGene_st:414266-HuGene_st:887612- HuGene_st:799837-HuGene_st:177635- HuGene_st:715579-HuGene_st:709222- HuGene_st:968483-HuGene_st:1030986- HuGene_st:327643-HuGene_st:540230- HuGene_st NR3C2 100953-HuGene_st:239673_at:981978- NR3C2 0.0129 1.1951 1.63 72.5 59.9-82.7 HuGene_st MLPH 218211_s_at MLPH 0.0138 1.2275 1.59 73 60.5-83.2 UGT1A1 208596_s_at:221305_s_at:204532_x_at:232654_s_at UGT1A3 0.0376 1.0578 1.68 70.2 57.5-80.8 MUC4 NA MUC4:TAF5L:LOC650855:LOC645744 0.0453 1.1986 1.31 72.6 60.1-82.8 KLF4 NA KLF4 0.0731 1.0018 1.58 69.2 56.5-79.9 CAPN9 NA CAPN9 0.074 0.9979 1.84 69.1 56.4-79.9 SELENBP1 NA SELENBP1 0.0902 0.9777 2 68.8 56.1-79.6 ATP8B1 NA ATP8B1 0.093 1.0347 1.4 69.8 57.2-80.4 WDR51B NA WDR51B 0.1284 1.0004 1.28 69.2 56.5-80  PBLD NA PBLD 0.1655 0.8731 1.89 66.9 54.1-78  ID1 NA ID1 0.2342 0.7662 1.66 64.9 52.2-76.2 CTSE NA CTSE 0.2809 0.7409 3.23 64.4 51.7-75.8 C6orf105 NA C6orf105 0.7794 0.7003 1.37 63.7 50.8-75.1

TABLE 8 Gene Symbol ValidPS_UP Symbol Signif. FDR D. val5 FC Sens-Spec CI (95) SPARC 677215-HuGene_st:456544- SPARC 3.0479E−09 2.3799 3.24 88.3 78.1-94.6 HuGene_st:1041514-HuGene_st:868223- HuGene_st:1053181-HuGene_st:196416- HuGene_st:1078055-HuGene_st:213861- HuGene_st:452422-HuGene_st:1078242- HuGene_st:497056-HuGene_st:1285- HuGene_st:793848-HuGene_st:455765- HuGene_st:72235-HuGene_st:568912- HuGene_st:887159-HuGene_st:255885- HuGene_st:225477-HuGene_st:162094- HuGene_st:1026630-HuGene_st:200665_s_at COL4A2 540082-HuGene_st:295949- COL4A2 5.5315E−09 2.4297 2.87 88.8 78.6-95  HuGene_st:1009411-HuGene_st:245530- HuGene_st:834880-HuGene_st:801333- HuGene_st:500428-HuGene_st:990355- HuGene_st:469754-HuGene_st:980150- HuGene_st:184258-HuGene_st:580118- HuGene_st:281233-HuGene_st:732269- HuGene_st:1075712-HuGene_st:643598- HuGene_st:772366- HuGene_st:211966_at:512520- HuGene_st:973004-HuGene_st:839631- HuGene_st:211964_at:316644- HuGene_st:1015712-HuGene_st COL4A1 831741-HuGene_st:634068- COL4A1  1.243E−08 2.3004 3.03 87.5  77-94.2 HuGene_st:816476-HuGene_st:1030276- HuGene_st:144637-HuGene_st:24196- HuGene_st:272762-HuGene_st:604042- HuGene_st:392785-HuGene_st:782962- HuGene_st:381555-HuGene_st:576333- HuGene_st:310901-HuGene_st:237606- HuGene_st:719873-HuGene_st:914012- HuGene_st:30564-HuGene_st:828024- HuGene_st:687375- HuGene_st:211981_at:211980_at:812556- HuGene_st:681655-HuGene_st:233652_at SPON2 173417-HuGene_st:845288- SPON2 1.9471E−08 2.3295 3.38 87.8 77.4-94.3 HuGene_st:170898-HuGene_st:6411- HuGene_st:981126-HuGene_st:1098117- HuGene_st:1049111-HuGene_st:1018834- HuGene_st:300655-HuGene_st:45524- HuGene_st:256565-HuGene_st:533681- HuGene_st:346131-HuGene_st:251693- HuGene_st:937110-HuGene_st:347749- HuGene_st:645379-HuGene_st:107844- HuGene_st:396405- HuGene_st:218638_s_at:156949_s_at COL5A2 631247-HuGene_st:59739- COL5A2 5.7658E−08 2.2164 3.31 86.6  76-93.5 HuGene_st:260654-HuGene_st:125943- HuGene_st:292068-HuGene_st:788391- HuGene_st:408375-HuGene_st:561511- HuGene_st:838505-HuGene_st:915389- HuGene_st:684636-HuGene_st:817279- HuGene_st:514415-HuGene_st:583557- HuGene_st:1009654-HuGene_st:416341- HuGene_st:260479-HuGene_st:292241- HuGene_st:1034540-HuGene_st:101178- HuGene_st:221730_at:221729_at FSTL1 1020674-HuGene_st:291086- FSTL1 7.8434E−08 2.2277 2.64 86.7 76.1-93.6 HuGene_st:964097-HuGene_st:874354- HuGene_st:745908-HuGene_st:129330- HuGene_st:1039443-HuGene_st:855602- HuGene_st:494940-HuGene_st:666633- HuGene_st:10001-HuGene_st:654906- HuGene_st:322189-HuGene_st:891629- HuGene_st:225280-HuGene_st:67871- HuGene_st:965246-HuGene_st BGN 722197-HuGene_st:1090822- BGN 9.6881E−08 2.2246 2.99 86.7 76.1-93.6 HuGene_st:45294-HuGene_st:381650- HuGene_st:987820-HuGene_st:978124- HuGene_st:171694-HuGene_st:643594- HuGene_st:429977-HuGene_st:1096605- HuGene_st:861988-HuGene_st:164623- HuGene_st:201262_s_at:497499- HuGene_st:422042-HuGene_st:1051954- HuGene_st:262594-HuGene_st:279145- HuGene_st:838396-HuGene_st:298959- HuGene_st:11448-HuGene_st:111675- HuGene_st:213905_x_at:201261_x_at:973749- HuGene_st FAP 58645-HuGene_st:581008- IFIH1:FAP  1.358E−07 2.2253 4.88 86.7 76.1-93.6 HuGene_st:284881-HuGene_st:1022038- HuGene_st:916010-HuGene_st:947725- HuGene_st:477772-HuGene_st:22772- HuGene_st:636840-HuGene_st:40379- HuGene_st:993707-HuGene_st:322964- HuGene_st:759386-HuGene_st:132558- HuGene_st:600137-HuGene_st:915847- HuGene_st:246189-HuGene_st:445095- HuGene_st:389696-HuGene_st:438119- HuGene_st:748913-HuGene_st:209955_s_at COL8A1 333339-HuGene_st:214587_at:586420- COL8A1 3.6053E−07 2.1439 3.09 85.8 74.9-93  HuGene_st:103513-HuGene_st:651142- HuGene_st:617293-HuGene_st:107398- HuGene_st:79621-HuGene_st:806363- HuGene_st:327074-HuGene_st:41199- HuGene_st COL1A1 767019-HuGene_st:654019- COL1A1 5.4426E−07 2.0142 3.29 84.3 73.1-92  HuGene_st:52480-HuGene_st:975188- HuGene_st:731985-HuGene_st:849620- HuGene_st:652845-HuGene_st:1077639- HuGene_st:149590-HuGene_st:788754- HuGene_st:1033327-HuGene_st:258815- HuGene_st:719132-HuGene_st:971026- HuGene_st:1061961-HuGene_st:435403- HuGene_st:498576-HuGene_st:1003153- HuGene_st:1029566-HuGene_st:487433- HuGene_st:165153-HuGene_st:125258- HuGene_st:217430_x_at:202310_s_(—) at:1556499_s_at:202311_s_at COL6A3 312177-HuGene_st:24239- COL6A3 5.7026E−07 2.0313 2.73 84.5 73.5-92.1 HuGene_st:337032-HuGene_st:31627- HuGene_st:72819-HuGene_st:85665- HuGene_st:51265-HuGene_st:315258- HuGene_st:423421-HuGene_st:976272- HuGene_st:627131-HuGene_st:547019- HuGene_st:482866-HuGene_st:871788- HuGene_st:273133-HuGene_st:945341- HuGene_st:223275-HuGene_st:768482- HuGene_st:618342-HuGene_st:993598- HuGene_st:716493-HuGene_st:153821- HuGene_st:201438_at COL1A2 918394-HuGene_st:75788- COL1A2:LOC728628 8.8466E−07 2.0613 2.62 84.9 73.9-92.3 HnGene_st:240155-HuGene_st:1079758- HuGene_st:174439-HuGene_st:133455- HuGene_st:720682-HuGene_st:723785- HuGene_st:1076123-HuGene_st:252002- HuGene_st:733200-HuGene_st:890123- HuGene_st:1070579-HuGene_st:52384- HuGene_st:928914-HuGene_st:257376- HuGene_st:355867-HuGene_st:472073- HuGene_st:349798-HuGene_st:153814- HuGene_st:825347- HuGene_st:202404_s_at:202403_s_at THY1 149448-HuGene_st:804495- THY1 1.0326E−06 1.9155 3.34 83.1 71.7-91.1 HuGene_st:287669-HuGene_st:329513- HuGene_st:432229-HuGene_st:834028- HuGene_st:462769-HuGene_st:408326- HuGene_st:603473-HuGene_st:497809- HuGene_st:301090-HuGene_st:606465- HuGene_st:208850_s_at:278686- HuGene_st:804789-HuGene_st:236645- HuGene_st:257047-HuGene_st:554409- HuGene_st:108391- HuGene_st:208851_s_at:213869_x_at:908785- HuGene_st:516398-HuGene_st COL15A1 330621-HuGene_st:910395- COL15A1 1.0611E−06 2.0128 3.37 84.3 73.2-92  HuGene_st:811192-HuGene_st:294092- HuGene_st:958891-HuGene_st:407270- HuGene_st:423090-HuGene_st:1079597- HuGene_st:95084-HuGene_st:775288- HuGene_st:813875-HuGene_st:1001637- HuGene_st:49304-HuGene_st:970691- HuGene_st:346838-HuGene_st:91483- HuGene_st:528528-HuGene_st:453998- HuGene_st:254490- HuGene_st:203477_at:201064-HuGene_st CALD1 816439-HuGene_st:318906- CALD1 1.1059E−06 2.1159 1.7 85.5 74.6-92.8 HuGene_st:558226-HuGene_st:755661- HuGene_st:519079-HuGene_st:1094139- HuGene_st:975649-HuGene_st:407536- HuGene_st:908350-HuGene_st:576686- HuGene_st:688034-HuGene_st:792918- HuGene_st:596642-HuGene_st:797317- HuGene_st:1023569-HuGene_st:450656- HuGene_st:231881_at:165931-HuGene_st IGFBP7 363517-HuGene_st:787689- IGFBP7 1.1574E−06 1.9989 1.91 84.1 72.9-91.8 HuGene_st:86333-HuGene_st:882867- HuGene_st:620969-HuGene_st:167271- HuGene_st:192752-HuGene_st:521467- HuGene_st:699448-HuGene_st:882712- HuGene_st:211325-HuGene_st:329940- HuGene_st:980809-HuGene_st:22805- HuGene_st:288233-HuGene_st:230028- HuGene_st:551901-HuGene_st:921418- HuGene_st:232544_at:969620- HuGene_st:985682-HuGene_st INHBA 1088123-HuGene_st:151327- INHBA 1.1943E−06 2.0051 3.38 84.2  73-91.9 HuGene_st:363337-HuGene_st:874496- HuGene_st:402595-HuGene_st:289422- HuGene_st:838338-HuGene_st:746887- HuGene_st:623455-HuGene_st:395552- HuGene_st:865665-HuGene_st:328796- HuGene_st:1088331-HuGene_st:751719- HuGene_st:36929-HuGene_st:548889- HuGene_st:909672- HuGene_st:210511_s_at:344276- HuGene_st:204926_at:112496-HuGene_st COL12A1 905983-HuGene_st:794749- TMEM30A:COL12A1 1.2492E−06 2.03 4.16 84.5 73.4-92.1 HuGene_st:1063560-HuGene_st:567963- HuGene_st:140178-HuGene_st:289954- HuGene_st:620694-HuGene_st:31736- HuGene_st:1009559-HuGene_st:435472- HuGene_st:415220-HuGene_st:447689- HuGene_st:405565-HuGene_st:180263- HuGene_st:595404-HuGene_st:759154- HuGene_st:419264-HuGene_st:319853- HuGene_st:225664_at:231879_at:874183- HuGene_st:913204- HuGene_st:231766_s_at:234951_s_at:1057284- HuGene_st COL5A1 64984-HuGene_st:815841- COL5A1 1.6076E−06 1.9335 2.75 83.3  72-91.3 HuGene_st:299983-HuGene_st:751853- HuGene_st:33784-HuGene_st:366345- HuGene_st:63200-HuGene_st:293998- HuGene_st:544275-HuGene_st:940629- HuGene_st:383962-HuGene_st:995286- HuGene_st:640471-HuGene_st:77586- HuGene_st:212489_at:633141- HuGene_st:203325_s_at:777727- HuGene_st:400357- HuGene_st:212488_at:291267- HuGene_st:285959-HuGene_st:886716- HuGene_st THBS2 789762-HuGene_st:451028- THBS2 2.3382E−06 1.9035 6.5 82.9 71.6-91  HuGene_st:807449-HuGene_st:895973- HuGene_st:360384-HuGene_st:885374- HuGene_st:178235-HuGene_st:241784- HuGene_st:774957-HuGene_st:565405- HuGene_st:684979-HuGene_st:890746- HuGene_st:588267-HuGene_st:1033680- HuGene_st:387904-HuGene_st:1096131- HuGene_st:739113-HuGene_st:614690- HuGene_st:270369-HuGene_st:892858- HuGene_st TNC 441837-HuGene_st:278723- TNC 3.7414E−06 1.9636 2.14 83.7 72.4-91.6 HuGene_st:1030770-HuGene_st:767997- HuGene_st:514659-HuGene_st:873244- HuGene_st:837401-HuGene_st:621609- HuGene_st:888816-HuGene_st:660419- HuGeue_st:889974-HuGene_st:780538- HuGene_st:157747-HuGene_st:908522- HuGene_st:263796-HuGene_st:280913- HuGene_st:201645_at:1016643- HuGene_st:243540_at:537682- HuGene_st:859608-HuGene_st:1079032- HuGene_st:458991-HuGene_st:241272_at MGP 148839-HuGene_st MGP:C12orf46 5.8225E−06 1.9994 2.62 84.1  73-91.9 COL31A1 410491-HuGene_st:718613- COL3A1 9.2906E−06 1.8484 2.32 82.2 70.8-90.5 HuGene_st:1083201-HuGene_st:364429- HuGene_st:857967-HuGene_st:714343- HuGene_st:977793-HuGene_st:295757- HuGene_st:22453-HuGene_st:804687- HuGene_st:682411-HuGene_st:490951- HuGene_st:622631-HuGene_st:782663- HuGene_st:425013-HuGene_st:214723- HuGene_st:86407-HuGene_st:651938- HuGene_st:403765-HuGene_st:376736- HuGene_st:376290-HuGene_st:248520- HuGene_st SULF1 740854-HuGene_st:517026- SULF1 0.000014436 1.7533 2.84 81 69.2-89.6 HuGene_st:933799-HuGene_st:72604- HuGene_st:1045684-HuGene_st:492122- HuGene_st:20084-HuGene_st:512275- HuGene_st:754502-HuGene_st:730003- HuGene_st:532406-HuGene_st:187508- HuGene_st:671986-HuGene_st:34752- HuGene_st:381424-HuGene_st:166879- HuGene_st:530745-HuGene_st:1018600- HuGene_st:212344_at:212354_at:482916- HuGene_st:212353_at HTRA1 660603-HuGene_st:252436- HTRA1 0.000017178 1.7312 2.29 80.7 68.9-89.3 HuGene_st:299850-HuGene_st:317595- HuGene_st:977390-HuGene_st:311841- HuGene_st:946172-HuGene_st:761215- HuGene_st:577479-HuGene_st:332527- HuGene_st:1082067-HuGene_st:981054- HuGene_st:5171-HuGene_st:1019008- HuGene_st:757466-HuGene_st:723015- HuGene_st LOXL2 937941-HuGene_st:827532- ENTPD4:LOXL2 0.000019895 1.7774 2.45 81.3 69.6-89.7 HuGene_st:346541-HuGene_st:271051- HuGene_st:228808_s_at:254550- HuGene_st:260752-HuGene_st:46172- HuGene_st:950166-HuGene_st:281266- HuGene_st:818138-HuGene_st:626390- HuGene_st:291104-HuGene_st:84360- HuGene_st:228823-HuGene_st:966956- HuGene_st:202997_s_at:898787- HuGene_st:202999_s_at:1074111- HuGene_st:1064065- HuGene_st:202998_s_at:328673- HuGene_st:1562263_at:34062-HuGene_st SULF2 367910-HuGene_st:661661- SULF2 0.000020766 1.6803 2.25 80 68.1-88.8 HuGene_st:43751-HuGene_st:395846- HuGene_st:771921-HuGene_st:550105- HuGene_st:195771-HuGene_st:435480- HuGene_st:229718-HuGene_st:826084- HuGene_st:262732-HuGene_st:848382- HuGene_st:861858-HuGene_st:907a57- HuGene_st:801956-HuGene_st:54769- HuGene_st:214147-HuGene_st:1034817- HuGene_st:929065- HuGene_st:233555_s_at:430325-HuGene_st MMP2 650123-HuGene_st:78720- MMP2 0.000025409 1.7328 3.02 80.7 68.8-89.3 HuGene_st:168982-HuGene_st:598990- HuGene_st:346729-HuGene_st:356008- HuGene_st:821467-HuGene_st:905494- HuGene_st:568028-HuGene_st:711286- HuGene_st:666575-HuGene_st:208210- HuGene_st:20913-HuGene_st:382005- HuGene_st:186287-HuGene_st:355238- HuGene_st:60728- HuGene_st:1566677_at:1027926- HuGene_st:38019-HuGene_st:39088- HuGene_st TIMP3 686923-HuGene_st:767021- TIMP3 0.000026195 1.7785 2.56 81.3 69.6-89.8 HuGene_st:231888_at:201148_s_at:326731- HuGene_st:72249-HuGene_st:369765- HuGene_st:711121-HuGene_st:844721- HuGene_st:856619-HuGene_st:241221- HuGene_st:515184-HuGene_st:948668- HuGene_st:410881-HuGene_st COL6A2 404866-HuGene_st:420794- COL6A2 0.000029551 1.7418 1.67 80.8  69-89.4 HuGene_st:536399-HuGene_st:813295- HuGene_st:160736-HuGene_st:501950- HuGene_st:148827-HuGene_st:501480- HuGene_st:375216-HuGene_st:143566- HuGene_st:1086501-HuGene_st:475436- HuGene_st:794188-HuGene_st:704415- HuGene_st:213290_at LOC387763 724781-HuGene_st:816467-HuGene_st LOC387753 0.00003052 1.8978 1.43 82.9 71.4-90.9 DKK3 573143-HuGene_st:509897- DKK3 0.000031838 1.7435 1.86 80.8 69.1-89.5 HuGene_st:829432-HuGene_st:425906- HuGene_st:1076690-HuGene_st:480668- HuGene_st:302214-HuGene_st:673860- HuGene_st:584666-HuGene_st:966441- HuGene_st:138862-HuGene_st:19243- HuGene_st:600102-HuGene_st:778172- HuGene_st:387542- HuGene_st:202196_s_at:230508_at:86457- HuGene_st CTSK 592586-HuGene_st:682010- CTSK 0.000039778 1.7156 2.16 80.4 68.8-89.1 HuGene_st:30909-HuGene_st:235976- HuGene_st:913861-HuGene_st:25198- HuGene_st:96515-HuGene_st:221416- HuGene_st:341005-HuGene_st:371949- HuGene_st:796154-HuGene_st:555578- HuGene_st:416489-HuGene_st:123013- HuGene_st:50644-HuGene_st:636682- HuGene_st:63600-HuGene_st:356075- HuGene_st:321593-HuGene_st LOC541471 19600-HuGene_st:149287- MGC4677, 0.000041139 1.804 1.45 81.6 69.9-90  HuGene_st:916693-HuGene_st:569637- MGC4677:LOC541471 HuGene_st:868769-HuGene_st:469295- HuGene_st:277416-HuGene_st:71551- HuGene_st:1558836_at:129947- HuGene_st:644672-HuGene_st:276744- HuGene_st:873188-HuGene_st:830227- HuGene_st:101170-HuGene_st:624891- HuGene_st:85671-HuGene_st:236489- HuGene_st:709116-HuGene_st:279980- HuGene_st:812194-HuGene_st CHI3L1 561691-HuGene_st:116044- CHI3L1:MYBPH 0.000051515 1.6351 3.06 79.3 67.4-88.3 HuGene_st:261087-HuGene_st:57128- HuGene_st:970931-HuGene_st:518568- HuGene_st:362438-HuGene_st:388847- HuGene_st:738096- HuGene_st:209396_s_at:171378- HuGene_st:968794-HuGene_st:477315- HuGene_st:852388-HuGene_st:90371- HuGene_st:209395_at:657732- HuGene_st:1050574-HuGene_st:1074100- HuGene_st:219902-HuGene_st:744799- HuGene_st CD93 392816-HuGene_st:131787- CD93 0.000051891 1.6662 2.36 79.8 67.8-88.6 HuGene_st:900048-HuGene_st:1024597- HuGene_st:449159-HuGene_st:937408- HuGene_st:835153-HuGene_st:231835- HuGene_st:1084191-HuGene_st:970338- HuGene_st:835439-HuGene_st:345929- HuGene_st:310915-HuGene_st:381822- HuGene_st:627382-HuGene_st:731932- HuGene_st COL11A1 372742-HuGene_st:523307- COL11A1 0.000053391 1.7583 2.55 81 69.3-89.5 HuGene_st:360134-HuGene_st:64257- HuGene_st:633985-HuGene_st:986684- HuGene_st:2674-HuGene_st:575064- HuGene_st:1023506-HuGene_st:198973- HuGene_st:20543-HuGene_st:254341- HuGene_st:81512-HuGene_st:549979- HuGene_st:347332-HuGene_st LBH 764120-HuGene_st:189486- LBH 0.000063299 1.6753 1.9 79.9 67.9-88.7 HuGene_st:766856-HuGene_st1083711- HuGene_st:541408-HuGene_st:375190- HuGene_st:938798-HuGene_st:133862- HuGene_st:956722-HuGene_st:97472- HuGene_st:19277-HuGene_st OLFML2B 1085957-HuGene_st:354052- OLFML2B 0.000066557 1.705 1.97 80.3 68.5-89  HuGene_st:682043-HuGene_st:249054- HuGene_st:867838-HuGene_st:430882- HuGene_st:704400-HuGene_st:1065400- HuGene_st:588559-HuGene_st:827842- HuGene_st:272527-HuGene_st:134966- HuGene_st:523921-HuGene_st:895516- HuGene_st:1022747-HuGene_st:529564- HuGene_st:539568-HuGene_st:427677- HuGene_st:122501-HuGene_st MMP1 524115-HuGene_st:689073- MMP1 0.000070616 1.6771 3.91 79.9 68.1-88.7 HuGene_st:300572-HuGene_st:914223- HuGene_st:958445-HuGene_st:61706- HuGene_st:437171-HuGene_st:422476- HuGene_st:361198-HuGene_st:693724- HuGene_st:671620-HuGene_st:673683- HuGene_st:1020786-HuGene_st:732367- HuGene_st:710307-HuGene_st:445730- HuGene_st:622653-HuGene_st:468477- HuGene_st:1070117-HuGene_st:840324- HuGene_st:473664-HuGene_st PALM2-AKAP2 945487-HuGene_st:454513- AKAP2:PALM2:PALM2- 0.000074206 1.724 1.58 80.6 68.9-89.2 HuGene_st:799637-HuGene_st:91787- AKAP2 HuGene_st:448601-HuGene_st:839008- HuGene_st:1044350-HuGene_st:327679- HuGene_st:665040-HuGene_st:79769- HuGene_st:216125-HuGene_st:205232- HuGene_st:818531-HuGene_st:169199- HuGene_st:537891-HuGene_st:667958- HuGene_st:202760_s_at FBN1 288955-HuGene_st:112593- FBN1 0.0001 1.5949 1.48 78.7 66.7-87.8 HuGene_st:427611-HuGene_st:921008- HuGene_st:82155-HuGene_st:828273- HuGene_st:999573-HuGene_st:192029- HuGene_st:162818-HuGene_st:794561- HuGene_st:316216-HuGene_st:971683- HuGene_st:394963-HuGene_st:600623- HuGene_st:169932-HuGene_st:941525- HuGene_st:202765_s_at:1094040- HuGene_st:192231-HuGene_st:235318_at MMP3 7912-HuGene_st:438906- MMP3 0.0001 1.6224 6.68 79.1 67.2-88.1 HuGene_st:483424-HuGene_st:634624- HuGene_st:191436-HuGene_st:542596- HuGene_st:664043-HuGene_st:766524- HuGene_st:134417-HuGene_st:945713- HuGene_st:149350-HuGene_st:357556- HuGene_st:206224-HuGene_st:560206- HuGene_st:822598-HuGene_st:200029- HuGene_st:701539-HuGene_st:526573- HuGene_st:35444-HuGene_st ISLR 1034362-HuGene_st:755902- ISLR 0.0001 1.6424 1.87 79.4 67.4-88.4 HuGene_st:864958-HuGene_st:599962- HuGene_st:207191_s_at:256349- HuGene_st:223953-HuGene_st:172743- HuGene_st:46312-HuGene_st:11475- HuGene_st:500169-HuGene_st COL6A1 138884-HuGene_st:100156- COL6A1 0.0001 1.7314 1.58 80.7 68.9-89.3 HuGene_st:694215-HuGene_st:133534- HuGene_st:354247-HuGene_st:737256- HuGene_st:214200_s_at:212939_at:216904_at:884210- HuGene_st:57954-HuGene_st:138366- HuGene_st:175316-HuGene_st:459478- HuGene_st:190064-HuGene_st:914102- HuGene_st:392220- HuGene_st:212937_s_at:125972- HuGene_st:214513-HuGene_st:528191- HuGene_st:858575- HuGene_st:212938_at:212091_s_at:212940_at:871472- HuGene_st FNDC1 194684-HuGene_st:358155- FNDC1 0.0001 1.5241 3.14 77.7 65.6-87  HuGene_st:959100-HuGene_st:187071- HuGene_st:449250-HuGene_st:879569- HuGene_st:588958-HuGene_st:162623- HuGene_st:711103-HuGene_st:30750- HuGene_st:34787-HuGene_st:260399- HuGene_st:418036-HuGene_st AEBP1 479622-HuGene_st:192126- AEBP1 0.0002 1.4786 2.11 77 64.8-86.4 HuGene_st:209682-HuGene_st:285969- HuGene_st:1041745-HuGene_st:668627- HuGene_st:913865-HuGene_st:944753- HuGene_st:446850-HuGene_st:118310- HuGene_st:342980-HuGene_st:845095- HuGene_st:185307-HuGene_st:901268- HuGene_st:494284-HuGene_st:201792_at:51739- HuGene_st:262459-HuGene_st MMP11 203878_s_at:213602_s_at:203877_at:324921- MMP11 0.0002 1.6993 1.28 80.2 68.3-89  HuGene_st:718792-HuGene_st:514533- HuGene_st:720030-HuGene_st:935371- HuGene_st:844472-HuGene_st:548687- HuGene_st:519881-HuGene_st:858774- HuGene_st:943793-HuGene_st:671549- HuGene_st:127919-HuGene_st:670295- HuGene_st:235908_at:203876_s_at:986917- HuGene_st:155442-HuGene_st:1036101- HuGene_st IGFBP5 532497-HuGene_st:823295- IGFBP5 0.0002 1.5676 3.96 78.3 66.4-87.5 HuGene_st:323206-HuGene_st:941332- HuGene_st:723182-HuGene_st:301318- HuGene_st:1007784-HuGene_st:503864- HuGene_st:492730-HuGene_st:370183- HuGene_st:867094-HuGene_st:965814- HuGcne_st:778210- HuGene_st:203425_s_at:692986- HuGene_st:1006982-HuGene_st:807775- HuGene_st:1035577-HuGene_st:158302- HuGene_st:73598- HuGene_st:1555997_s_at:231985- HuGene_st:203424_s_at:211958_at:203426_s_at:334486- HuGene_st:383523-HuGene_st PLAU 611756-HuGene_st:246040- PLAU 0.0003 1.4846 2.11 77.1 64.8-86.5 HuGene_st:783863-HuGene_st:1027344- HuGene_st:186016-HuGene_st:31176- HuGene_st:692506-HuGene_st:52541- HuGene_st:205479_s_at:471777- HuGene_st:156254-HuGene_st:1085903- HuGene_st:211668_s_at:131855- HuGene_st:585614-HuGene_st:1076162- HuGene_st:323438-HuGene_st:410729- HuGene_st CTHRC1 647908-HuGene_st:235232- CTHRC1 0.0003 1.4612 3.41 76.7 64.5-86.2 HuGene_st:86783-HuGene_st:756615- HuGene_st:779928-HuGene_st:385407- HuGene_st:978256-HuGene_st:607929- HuGene_st:426340-HuGene_st FN1 1002635-HuGene_st:585884- FN1 0.0003 1.4907 2.87 77.2  65-86.6 HuGene_st:338536-HuGene_st:586400- HuGene_st:445068-HuGene_st:395670- HuGene_st:19848-HuGene_st:443264- HuGene_st:662053-HuGene_st:144815- HuGene_st:103145-HuGene_st:372804- HuGene_st:652840-HuGene_st:935697- HuGene_st:484350-HuGene_st:422572- HuGene_st:814551-HuGene_st:235724- HuGene_st:214701_s_at:692191- HuGene_st:132330- HuGene_st:210495_x_at:639087- HuGene_st:216442_x_at:211719_x_(—) at:214702_at:212464_s_at:1558199_at RAB31 784521-HuGene_st:805481- RAB31 0.0003 1.4857 2.08 77.1  65-86.6 HuGene_st:936297-HuGene_st:576193- HuGene_st:321915-HuGene_st:282618- HuGene_st:930765-HuGene_st:397177- HuGene_st:861778-HuGene_st:411822- HuGene_st:240571_at:816751- HuGene_st:1028297-HuGene_st:291722- HuGene_st:722575-HuGene_st:904649- HuGene_st:991710-HuGene_st:1032281- HuGene_st:217764_s_at:252384-HuGene_st LGALS1 540889-HuGene_st:882911- LGALS1 0.0004 1.4863 1.61 77.1 64.8-86.5 HuGene_st:289133-HuGene_st:775286- HuGene_st:179375-HuGene_st:877452- HuGene_st:697650-HuGene_st:1720- HuGene_st:107624-HuGene_st:810235- HuGene_st:190535-HuGene_st:529287- HuGene_st:725969-HuGene_st:976579- HuGene_st:1075722-HuGene_st:453861- HuGene_st:216405_at:624673- HuGene_st:724499-HuGene_st ELOVL5 559433-HuGene_st:422981- ELOVL5 0.0004 1.542 1.86 78 65.8-87.2 HuGene_st:211457-HuGene_st:551828- HuGene_st:412588-HuGene_st:912245- HuGene_st:287185-HuGene_st:103066- HuGene_st:399004-HuGene_st:528360- HuGene_st:938564-HuGene_st:1000247- HuGene_st:620190-HuGene_st:336885- HuGene_st:165821- HuGene_st:214153_at:731356- HuGene_st:601072-HuGene_st:755480- HuGene_st:8873- HuGene_st:1567222_x_at:208788_at:1093316- HuGene_st ANTXR1 203217-HuGene_st:501276- ANTXR1 0.0005 1.5167 2 77.6 65.4-86.9 HuGene_st:799524-HuGene_st:85875- HuGene_st:12099-HuGene_st:230429- HuGene_st:368173-HuGene_st:369297- HuGene_st:227660_at:86683- HuGene_st:682518-HuGene_st:129277- HuGene_st:827509-HuGene_st:901442- HuGene_st:408237-HuGene_st:414321- HuGene_st:330209- HuGene_st:234430_at:241549_at:755570- HuGene_st:220093_at ACTA2 479447-HuGene_st:183075- ACTA2  6.00E−04 1.4242 1.75 76.2 63.8-85.8 HuGene_st:1070983-HuGene_st:548186- HuGene_st:529704-HuGene_st:530590- HuGene_st:630797-HuGene_st:404109- HuGene_st:237159-HuGene_st:90357- HuGene_st:293590-HuGene_st:1078299- HuGene_st:120087-HuGene_st:855050- HuGene_st:757548-HuGene_st:980364- HuGene_st:785232-HuGene_st:313690- HuGene_st:670805-HuGene_st IGFBP3 242422-HuGene_st:1046998- IGFBP3 0.0006 1.552 1.38 78.1  66-87.3 HuGene_st:585931-HuGene_st:145671- HuGene_st:71362-HuGene_st:719466- HuGene_st:412306-HuGene_st:922332- HuGene_st:491408-HuGene_st:929740- HuGene_st:276131-HuGene_st:201952- HuGene_st VIM 1093618-HuGene_st:398387- VIM 0.0008 1.4804 1.48 77 64.9-86.5 HuGene_st:837477-HuGene_st:1079757- HuGene_st:339807-HuGene_st:302722- HuGene_st:139661-HuGene_st:436158- HuGene_st:564251-HuGene_st:234475- HuGene_st:770617-HuGene_st:155888- HuGene_st:319318-HuGene_st:527110- HuGene_st:994975-HuGene_st:192324- HuGene_st ASPN 720939-HuGene_st:96944- ASPN 0.0009 1.4011 2.75 75.8 63.5-85.6 HuGene_st:224396_s_at:640448- HuGene_st:1055545-HuGene_st:447994- HuGene_st:835521-HuGene_st:567513- HuGene_st:546047- HuGene_st:219087_at:673620-HuGene_st HNT 291569-HuGene_st:1099035- HNT 0.001 1.425 2.26 76.2 63.8-85.8 HuGene_st:237480- HuGene_st:222020_s_at:959054- HuGene_st:941200-HuGene_st:715332- HuGene_st:761810-HuGene_st:673027- HuGene_st:653559- HuGene_st:241934_at:403764- HuGene_st:719722-HuGene_st:227566_at GJA1 210697-HuGene_st:348617- GJA1 0.0013 1.4083 1.63 75.9 63.7-85.6 HuGene_st:100706-HuGene_st:202715- HuGene_st:817684-HuGene_st:851453- HuGene_st:317083-HuGene_st:852817- HuGene_st:150947-HuGene_st:491742- HuGene_st:612542-HuGene_st:352375- HuGene_st:684816-HuGene_st MSN 77554-HuGene_st:103225- MSN  1.40E−03 1.4927 1.36 77.2 65.1-86.7 HuGene_st:1038630-HuGene_st:555838- HuGene_st:250445-HuGene_st:770842- HuGene_st:240960_at:905037- HuGene_st:693942-HuGene_st:788076- HuGene_st:102934-HuGene_st:686613- HuGene_st SFRP4 965138-HuGene_st:512201- SFRP4 0.0015 1.407 2.2 75.9 63.5-85.5 HuGene_st:321583-HuGene_st:784119- HuGene_st:4568-HuGene_st:1073348- HuGene_st:606783-HuGene_st:203475- HuGene_st:779727-HuGene_st:236875- HuGene_st:674172- HuGene_st:204051_s_at:1084814- HuGene_st CTGF 418229-HuGene_st:547481- CTGF 0.0015 1.334 1.78 74.8 62.4-84.6 HuGene_st:661089-HuGene_st:338622- HuGene_st:353524-HuGene_st:466254- HuGene_st:691815-HuGene_st:156933- HuGene_st:1031177-HuGene_st:265466- HuGene_st:1079612-HuGene_st:1073900- HuGene_st:1080114-HuGene_st FCGR3B 775320-HuGene_st:483078- FCGR3B 0.0026 1.232 2.14 73.1 60.5-83.3 HuGene_st:897088-HuGene_st:891504- HuGene_st:288407-HuGene_st:367930- HuGene_st:512343-HuGene_st:524627- HuGene_st:290249- HuGene_st:204007_at:993144- HuGene_st:1084295-HuGene_st:606544- HuGene_st:160442-HuGene_st:974942- HuGene_st:582410-HuGene_st:117174- HuGene_st LOXL1 244262-HuGene_st:240421- LOXL1 0.0027 1.4045 1.33 75.9 63.7-85.5 HuGene_st:999775-HuGene_st LUM 253522-HuGene_st:646969- LUM 0.0029 1.3426 2.18 74.9 62.5-84.7 HuGene_st:566007-HuGene_st:629878- HuGene_st:346266-HuGene_st:749731- HuGene_st:848594-HuGene_st:781980- HuGene_st:838285-HuGene_st:594339- HuGene_st:1095278-HuGene_st:450762- HuGene_st:205322-HuGene_st:130751- HuGene_st:183047-HuGene_st:15672- HuGene_st SERPINF1 837342-HuGene_st SERPINF1 0.0031 1.2108 1.76 72.8 60.2-83  MXRA5 319799-HuGene_st:432137- MXRA5 0.0034 1.2959 1.62 74.1 61.6-84.1 HuGene_st:408065-HuGene_st:291182- HuGene_st:549236-HuGene_st:217706- HuGene_st:260019-HuGene_st:1079370- HuGene_st:216837-HuGene_st:607674- HuGene_st:829671-HuGene_st:348569- HuGene_st:357055-HuGene_st:394366- HuGene_st:192313-HuGene_st:124763- HuGene_st POSTN 954838-HuGene_st:153510- POSTN 0.005 1.301 2.58 74.2 61.7-84.3 HuGene_st:538299-HuGene_st:649547- HuGene_st:779754-HuGene_st:106590- HuGene_st:636479-HuGene_st:874100- HuGene_st:13993-HuGene_st:417058- HuGene_st:724846-HuGene_st:588010- HuGene_st:608772- HuGene_st:210809_s_at:743877- HuGene_st:713459-HuGene_st:713707- HuGene_st:753556-HuGene_st:776445- HuGene_st:388659-HuGene_st TAGLN 613243-HuGene_st:823959- TAGLN 0.0051 1.1811 2.19 72.3 59.6-82.6 HuGene_st:898711-HuGene_st:505391- HuGene_st:26929-HuGene_st:458482- HuGene_st:66114-HuGene_st:304704- HuGene_st:543865- HuGene_st:226523_at:270642- HuGene_st:179049-HuGene_st:279405- HuGene_st:902958-HuGene_st:931316- HuGene_st NNMT 231559_at:588888-HuGene_st:160284- NNMT 0.0054 1.2225 1.44 72.9 60.5-83.2 HuGene_st:591616-HuGene_st:968910- HuGene_st:789017-HuGene_st:218836- HuGene_st:775762- HuGene_st:202238_s_at:95357- HuGene_st:1098599-HuGene_st:793701- HuGene_st IL8 471213-HuGene_st:373132-HuGene_st LOC731467:C6orf142:CCDC42:IFI6:TRBV21- 0.0062 1.6808 1.33 80 68.1-88.7 1:H2AFZ:RNF20:TRBV5-4:TRBC1:TRBV3- 1:TRBV19:TRBV7-2:IL23A GREM1 651822-HuGene_st:546941- GREM1 0.007 1.3044 1.31 74.3 61.8-84.2 HuGene_st:639839-HuGene_st:326978- HuGene_st:593695-HuGene_st:127360- HuGene_st:407017-HuGene_st:1081939- HuGene_st:345681-HuGene_st:292333- HuGene_st:864620-HuGene_st:2445- HuGene_st:556201-HuGene_st:569365- HuGene_st:411208-HuGene_st:330742- HuGene_st C1S 947234-HuGene_st:962144- C1S 0.0088 1.3551 1.77 75.1 62.8-84.9 HuGene_st:567397-HuGene_st:490300- HuGene_st:459367-HuGene_st:1059233- HuGene_st:915378-HuGene_st:682561- HuGene_st:881984-HuGene_st:332123- HuGene_st:37033-HuGene_st:433793- HuGene_st:564959-HuGene_st:240802- HuGene_st:245571-HuGene_st:156493- HuGene_st:186313-HuGene_st:866948- HuGene_st:661278-HuGene_st:665064- HuGene_st:615340-HuGene_st:981405- HuGene_st:127169-HuGene_st:224321- HuGene_st:426716-HuGene_st:905688- HuGene_st:1009344-HuGene_st:184395- HuGene_st TIMP2 310783-HuGene_st:526357- TIMP2 0.0097 1.1623 1.72 71.9 59.4-82.3 HuGene_st:965142-HuGene_st:463158- HuGene_st:563754-HuGene_st:914626- HuGene_st:106688-HuGene_st:1087828- HuGene_st:740790-HuGene_st:799495- HuGene_st SPP1 87046-HuGene_st:904296- SPP1 0.0109 1.0677 3.91 70.3 57.6-80.9 HuGene_st:809583-HuGene_st:44881- HuGene_st:1568574_x_at:459132- HuGene_st:963342-HuGene_st:909306- HuGene_st:1070547-HuGene_st:31302- HuGene_st:975259-HuGene_st:743585- HuGene_st:530424-HuGene_st:709614- HuGene_st:1022539-HuGene_st:575437- HuGene_st:809262-HuGene_st:259921- HuGene_st SCD 214388-HuGene_st:1054693- SCD:LOC651109:LOC645313  1.27E−02 1.073 2.33 70.4 57.7-81  HuGene_st:433956-HuGene_st:1088784- HuGene_st:1019041-HuGene_st:698268- HuGene_st:64902-HuGene_st:749928- HuGene_st:713000-HuGene_st:562893- HuGene_st MYL9 206106-HuGene_st:608837- MYL9 0.0131 1.1754 1.37 72.2 59.6-82.4 HuGene_st:706186-HuGene_st:874422- HuGene_st:543240-HuGene_st:676360- HuGene_st:117460-HuGene_st:404703- HuGene_st:979054- HuGene_st:244149_at:467647- HuGene_st:925187-HuGene_st:173220- HuGene_st:923797-HuGene_st CD163 967100-HuGene_st:180883- CD163 0.0146 1.1667 2.19 72 59.4-82.3 HuGene_st:900552-HuGene_st:662901- HuGene_st:217692-HuGene_st:74082- HuGene_st:620892-HuGene_st:899841- HuGene_st:97726-HuGene_st S100A8 508168-HuGene_st:306748- S100A8 0.0148 1.1001 3.17 70.9 58.3-81.3 HuGene_st:473960-HuGene_st:98947- HuGene_st:777038-HuGene_st:233365- HuGene_st:671798-HuGene_st:214328- HuGene_st:214370_at:368299- HuGene_st:16960-HuGene_st:627642- HuGene_st:669207-HuGene_st:75346- HuGene_st:521635-HuGene_st:215650- HuGene_st:618819-HuGene_st CYR61 709380-HuGene_st:788428- CYR61 0.015 1.093 1.69 70.8 58.2-81.3 HuGene_st:385534-HuGene_st:924057- HuGene_st:951763-HuGene_st:48239- HuGene_st:462225-HuGene_st:789527- HuGene_st:673588-HuGene_st:306375- HuGene_st MAFB 883249-HuGene_st MAFB 0.0182 1.1589 1.48 71.9 59.3-82.3 APOE 555956-HuGene_st:99757-HuGene_st APOE 0.0285 1.1117 1.43 71.1 58.6-81.5 DCN 570449-HuGene_st:1067446-HuGene_st DCN 0.0364 1.0819 1.29 70.6  58-81.1 G0S2 888942-HuGene_st:346957- G0S2 0.0383 0.9923 1.53 69 56.3-79.9 HuGene_st:62728-HuGene_st:334340- HuGene_st:897401-HuGene_st CDH11 60296-HuGene_st:609892- CDH11 0.0384 1.01 1.98 69.3 56.7-80  HuGene_st:167614-HuGene_st:184349- HuGene_st:546348-HuGene_st:960949- HuGene_st:583244-HuGene_st:599824- HuGene_st:626011-HuGene_st:96018- HuGene_st:217538-HuGene_st:180379- HuGene_st SQLE 861626-HuGene_st:198540- SQLE 0.041 1.0133 2.15 69.4 56.7-80.1 HuGene_st:1010566-HuGene_st:895693- HuGene_st:967759-HuGene_st:894379- HuGene_st:827097-HuGene_st GPNMB NA GPNMB 0.0623 1.0155 1.52 69.4 56.8-80.1 KIAA1913 NA KIAA1913 0.1061 0.9593 1.2 68.4 55.7-79.3 SFRP2 NA SFRP2 0.1336 0.9696 1.24 68.6  56-79.4 SMOC2 NA SMOC2 0.2175 0.6581 2.06 62.9  50-74.4 SERPING1 NA SERPING1  2.64E−01 0.7805 1.26 65.2 52.5-76.5 EFEMP1 NA EFEMP1 0.4911 0.6831 1.27 63.4 50.5-74.9 TYROBP NA TYROBP 0.4923 0.7065 1.23 63.8 51.1-75.2 PLOD2 NA PLOD2 0.5151 0.7775 1.51 65.1 52.3-76.3

TABLE 9 SEQ ID Probe NO: Set ID Target Sequence 1 200660_ caaggctgggccgggaagggcgtgggagaggagaggctccagacccgcacgccgcgcgcacagagctctcagc at gccgctcccagccacagcctcccgcgcctcgctcagctccaacatggcaaaaatctccagccctacagagactgagc ggtgcatcgagtccctgattgctgtcaccagaagtatgctggaaaggatggttataactacactctctccaagacagagtt cctaagcttcatgaatacagaactagctgccacacaaagaaccagaaggaccctggtgtccttgaccgcatgatgaaga aactggacaccaacagtgatggtcagctagatactcagaatacttaatctgattggtggcctagctatggcttgccatgac tccacctcaaggctgtcccacccagaagcggacctgaggaccc 2 200665_ gttggttcaaacttttgggagcacggactgtcagactctgggaagtggtcagcgcatcctgcagggcactcctcctctgt s_at cttttggagaaccagggctcttctcaggggctctagggactgccaggctgtttcagccaggaaggccaaaatcaagagt gagatgtagaaagttgtaaaatagaaaaagtggagttggtgaatcggttgttctttcctcacatttggatgattgtcataagg tattagcatgacctccattatcaccctcccattgacttctattaatcaagagaaacttcaaagttaatgggatggtcggat ctcacaggctgagaactcgttcacctccaagcatttcatgaaaaagctgatcttattaatcatacaaactctcaccatgatg tg 3 200832_ aaaagcgaggtggccatgttatgctggtggagccagggcctccaaccactgtgccactgacttgctgtgtgaccctggg s_at caagtcacttaactataaggtgcctcagattccactgttaaaatggggataataatactgacctacctcaaagggcagatt gaggcatgactaatgctattagaaagcattagggatccacagcacaggaattctcaagacctgagtattattataatagg aatgtccaccatgaacttgatacgtccgtgtgtcccagatgctgtcattagtctatatggactccaagaaactgaatgaatc cattggagaagcggtggataactagccagacaaaatttgagaatacataaacaacgcattgccacggaaacatacaga ggatgccttttctgtgattgggtgggattttttccctttttatgtgggatatagtagttacttgtgacaagaataattttggaataa tactattaatatcaactctgaagctaattgtactaatctgagat 4 200903_ gcagcgggaacagagtaccctatcaagccccggtcatgatggaggtcccagccacagggaaccatgagctcagtgg s_at tcaggaacagctcactaagtcagtccaccttagcctggaagccagtagtggagtcacaaagcccatgtgattgccatct aggccacacctggtctgtggacttatacctgtgtgcaggatacaggtccagtggacttcagcccatgacagatgagaa ggggctatattgaagggcaaagaggaactgttgtttgaattttcctgagagcctggcttagtgctgggccttctcttaaacc tcattacaatgaggttagtacttttagtccctgt 5 201014_ agtgagatgggctctacactgatcaggtcactgtgaaaaaatcaagaaggcctgtggaaattaggcattccatgtgaac s_at ttcgagtaacatctgcgcataaaggaccagatgaaactctgaggattaaagctgagtatgaaggggatggcattcctact gtatagtggcagtggcaggcagaagtaatggtagggaccagtgatgtctgggaacactgcatatccagttatcagc 6 201112_ agatctgtgcggaggcataaccaacttactaacagaatgtcccccaatgatggacactgagtataccaaactgtggactc s_at cattattacagtattgattggtctattgagttacccgaagatgataccattcctgatgaggaacatatattgacatagaagat acaccaggatatcagactgccactcacagaggcatttgctgggaaaaaagagcatgatcctgtaggtcaaatggtgaat aaccccaaaattcacctggcacagtcacttcacatgagtctaccgcctgtccaggaagggttc 7 201195_ tcagaaggtaggggccgtgtcccgcggtgctgactgaggcctgcttccccctccccctcctgctgtgctggaattccaca s_at gggaccagggccaccgcaggggactgtctcagaagacttgattatccgtccattactccacactccactgacaaacgt ccccagcggtaccacttgtgggcttcaggtgattcaagcacaacccaccacaacaagcaagtgcattacagtcgagtg cattagattgtgctaacgtcttactaatttaaagatgctgtcggcaccatgatatttataccagtggtcatgctcagccagc tgctctgcgtggcgcaggtgccatgcctgctccctgtctgtgtcccagccacgcagggccatccactgtgacgtcggcc gaccaggctggacaccctctgccgagtaatgacgtgtgtggctgggaccactttattctgtgttaatggctaacctgttac actgggctgggagggtagggtgactggc 8 201261_ tctctctttctgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtcttgtgcttcctcagacctttctcgcttctgagcttggt x_at ggcctgaccctccatctctccgaacctggcttcgcctgtcccatcactccacaccctctggccactgccttgagctggga ctgctttctgtctgtccggcctgcacccagcccctgcccacaaaaccccagggacagcggtctccccagcctgccctgc tcaggccagcccccaaacctgtactgtcccggaggaggagggaggtggaggcccagcatcccgcgcagatgacac catcaaccgccagagtcccagacaccggattcctagaagcccctcacccccactggcccactggtggctaggtctccc cttatccactggtccagcgcaaggaggggctgatctgaggtcggtggctgtctaccattaaagaaacacc 9 201292_ tacagatactctactacactcagcctcttatgtgccaagtattattaagcaatgagaaattgctcatgacttcatcactcaa at atcatcagaggccgaagaaaaacactaggctgtgtctataacttgacacagtcaatagaatgaagaaaattagagtagtt atgtgattatttcagctcttgacctgtcccctctggctgcctctgagtctgaatctcccaaagagagaaaccaatactaaga ggactggattgcagaagactcggggacaacatttgatccaagatcttaaatgttatattgataaccatgctcagcaatgag ctattagattcattagggaaatctccataatttcaatagtaaactagttaagacctgtctacattgttatatg 10 201328_ agcatcggagccattcattcggagaaaacgattgatcaaaatggagacttagtagtcgatcaaaagagcacctgagtca at tgtgtattcccggcnnnattataaatgacccggtcaagaggatcaaagtncgacaggcagtctgatactagctgcgtg gccaggacgggtggctgacatctgtaaagaatcctcctgtgatgaaactgaggaatcgggtggccgggcaagctggg aagagcaaagccagnagctgcgctgcctcaatacccacaaaagaccattcccagtatacataagcacaggatgatact caagagggatgtatttatcacttggacatctgatataatataaacagacatgtgactgggaacatcagctgccaaaagaat cctaggcagtggctcattgtatgtgaggagaaccacgtgaaattgccaatattaggctggcattatctacaaagaaggag tacatggggacagcctaacagttatggaaactacagtccttataaaccattggcatg 11 201338_ gatgtatgtcgctgtccaagagaaggctgtggaagaacctatacaactgtgataatctccaaagccatatcctctccacc x_at atgaggaaagccgccatagtgtgtgaacatgctggctgtggcaaaacatttgcaatgaaacaaagtctcactaggcatg ctgagtacatgatcctgacaagaagaaaatgaagctcaaagtcaaaaaatctcgtgaaaaacgggagtaggcctctcat ctcagtggatatatcctcccaaaaggaaacaagggcaaggcttatctagtgtcaaaacggagagtcacccaactgtgtg gaagacaagatgctctcgacagagcagtacttacccaggctaagaactgcactgattgataaaggactgcagaccaa ggagtcgagctttctctca 12 201341_ ggtctgacttgaatcctctattaattactgtgtgtgagccagagggagctgtggtaagggagggcccccagcctgtagg at gaactactggactcccactattgaatcgatataggcataggtctcactacttgaccattctcaccctgtgaaacgtcccac actagaagcaaatacaattcacagcacagtacacacaaaaaccaggcataagacagagaaggacttcttattagtggg ctggagctgtagaaacatataacaaagggcagccctccacactggtataattgtgtagcccatttctagggcttgacac ctgtcttgaataagagtgattagagctgcataatgtccctctctt 13 201416_ gaggtcagataggagatctcattgcacgcggagattattattgcatcgggaccaagccaatgggaagcccggggga at ggggtaggcatgaggaagcgaggttacagcagctgattggctgcagccaagactgtgaaaggataaagaggcgcga ggcggaattggggtctgctctaagctgcagcaagagaaactgtgtgtgaggggaagaggcctgatcgctgtcgggtct ctagacttgcacgctattaagagtctgcactggaggaactcctgccattaccagctccatcttgcagaagggaggggg aaacatacatttattcatgccagtctgagcatgcaggctannggcacctaccagcaacaaaataattgcaccaactcctt agtgccgattccgcccacagagagtcctggagccacagtcttttttgctttgcattgtaggagagggactaagtgctagag actatgtcgctacctgagctaccgagagcgctcgtgaactggaatcaact 14 201417_ gtaaaccacatatattgcactatatataagcaaaaacgtgccgataaaccactggatctatctaaatgccgatttgagttc at gcgacactatgtactgcgtattcattcagtatttgactatttaatcattctacttgtcgctaaatataattgattagtcttatggc atgatgatagcatatgtgacaggatatagctgagtgataaaaattgaaaaaagtggaaaacatctagtacatttaagtct gtattataataagcaaaaagattgtgtgtatgtatgataatataacatgacaggcactaggacgtctgccatttaaggcagt tccgttaagggtattgatttaaactatattgccatccatcctgtgcaatatgccgtgta 15 201468_ gatgacttaccatgggatggggtccagtcccatgaccaggggtacaattgtaaacctagagattatcaactaggtgaac s_at agattggcataatagtcaatactacactggaagtcatctcattccactgaggtattatataattcaaggagaatatgataaa acactgccctcagtggtgcattgaaagaagagatgagaaatgatgaaaaggagcctgaaaaatgggagacagcctctt acttgccaagaaaatgaagggattggaccgagctggaaaacctcattaccagatgctgactggcactggtggtattgct ctcgacatatccacaatagctgacggctgggtgatcagtagcaaaatattagagcatcatatcactgcaattagtgta 16 201479_ ttcagacccagtaactgtccgcagctgtctgctagtggagtcttaacatcgtagtcctagtagcattattaaatcccctctgt at ttaaaaggtagtaaaacaaaaacaaaaaactaagtctgctcagtgaaatgctgtagaaccctaaataagtggtagaaga gtgtcactgaattttgtctctgaattcagtataactgagttttgtccatgctggtgtctgggttataggcctgatgggcctggta gattccatcttgactggcctagaggtcagtcattgcacttcctcaaagatgtgtacagtgctcacctaaatccatctgact acttgacctgtgccctcttgattaggcctcgatactataaaaaatgaaattgacattgctgggagaagaatgagtaattat acttattaaagtcaacttgttaagttttttatgtattcctgttgggttttcttgttg 17 201506_ acaggaggaatgcaccacggcagctctccgccaatactctcagataccacagagactgatgaatgattcaaaaccaa at gtatcacactttaatgtacatgggccgcaccataatgagatgtgagccagtgcatgtgggggaggagggagagagatg tactattaaatcatgaccccctaaacatggctgttaacccactgcatgcagaaacttggatgtcactgcctgacattcactt ccagagaggacctatcccaaatgtggaattgactgcctatgccaagtccctggaaaaggagcttcagtattgtggggctc ataaaacatgaatcaagcaatccagcctcatgggaagtcctggcacagtattgtaaagccatgcacagctggagaaat ggcatcattataagctatgagttgaaatgactgtcaaatgtgtctcacatctacacgtggcttggaggcattatggggccct gtccaggtagaaaagaaatggtatgtagagcttagataccctattgtgacagagcc 18 201563_ aggaaactgctacttgtggacctcaccagagaccaggagggtttggttagctcacaggacttcccccaccccagaagat at tagcatcccatactagactcatactcaactcaactaggctcatactcaattgatggttattagacaattccatactactggtta ttataaacagaaaatctacctcactcattaccagtaaaggctatggtatattctgaggaatgatttctatgaacttgtcttat ataatggtgggattattctggtaagatttagacctaaatcgcatcatgccaacttgtgactagagactattcatcaagaatg aggatatagtagccatgacatagcttgagctatagcattaattccttactaggctatgggtggagggtgagatgaagag gactgattacttgtaacctggga 19 201577_ gattccgccttgaggtctgaaattcatgcaagatccgaagatcactcaaggaacactacgttgacctgaaggaccgtcc at attattgccggcctggtgaaatacatgcactcagggccggtagagccatggtctgggaggggctgaatgtggtgaaga cgggccgagtcatgctcggggagaccaaccctgcagactccaagcctgggaccatccgtggagacactgcatacaa gaggcaggaacattatacatggcagtgattctgtggagagtgcagagaaggagatcggcagtggatcaccctgagga actggtagattacacgagctgtgctcagaactggatctatgaatgacaggagggcagaccacattgatttcacatccattt cccctccacccatgggcagaggaccaggctgtaggaaatctagttatttacaggaacttcatcataataggagggaagc tcttggagctgtgagttctccctgtacagtgttaccatc 20 201601_ agaaaaccacacactcataccacactcaacacttcatccccaaagccagaagatgcacaaggaggaacatgaggtg x_at gctgtgctgggggcaccccccagcaccatccttccaaggtccaccgtgattaacatccacagcgagacctccgtgccc gaccatgtcgtctggtccctgacaacaccctcacttgaactggtgctgtctgggcttcatagcattcgcctactccgtaaa gtctagggacaggaagatggaggcgacgtgaccggggcccaggcctatgcctccaccgccaagtgcctgaacatct gggccctgattctgggcatcctcatgaccattggattcatcctgttactggtattcggctctgtaacagtctaccatattatga acagataatacaggaaaaacggggttactagtagccgcccatagcctgcaaccatgcactccactgtgcaatgctggc c 21 201656_ gtagtgccactgagattggggggggctattactattccggaaaatccttaaaccttaagatactaaggacgttgattggt at tgtacttggaattcttagtcacaaaatatattagatacaaaaatactgtaaaacaggttataacagtgataaagtctcagat cttgatggggaacttgtgtccctaatgtgttagattgctagattgctaaggagctgatacttgacagttattagacctgtga actaaaaaaaagatgaatgtcggaaaagggtgagggagggtggtcaacaaagaaacaaagatgttatggtgatagac ttatggagttaaaaatgtcatctcaagtcaagtcactggtctgatgcatttgatacatttagtactaactagcattgtaaaatt atttcatgattagaaattacctgtggatatagtataaaagtgtgaaataaattattataaaagtgacattgatcgtaacacag catt 22 201666_ tcagggccaagttcgtggggacaccagaagtcaaccagaccaccttataccagcgttatgagatcaagatgaccaagat at gtataaagggaccaagccttaggggatgccgctgacatccggacgtctacacccccgccatggagagtgtctgcgga tacttccacaggtcccacaaccgcagcgaggagtactcattgctggaaaactgcaggatggactatgcacatcactac ctgcagatcgtggctccctggaacagcctgagcttagctcagcgccggggcttcaccaagacctacactgaggctgtg aggaatgcacagtgatccctgatatccatcccctgcaaactgcagagtggcactcattgatgtggacggacc 23 201925_ gtgattataccacaagatctgtaatgttatttccacttataaaggaaataaaaaatgaaaaacattatttggatatcaaaagc s_at aaataaaaacccaattcagtctcactaagcaaaattgctaaagagagatgaaccacattataaagtaatctaggctgtaa ggcattacatattcatcgggaggcaaaatatataaaggtaaaacatgctggtgaaccaggggtgagatggtgataag ggaggaatatagaatgaaagactgaatatcattgagcacaaatagagtaggaaaaagcctgtgaaaggtgtatatt gacttaatgtattaaaagtatccagagatactacaatattaacataagaaaagattatatattatactgaatcgagatgtcca tagtcaaatttgtaa 24 201926_ gagagcactctatttattgtactgtgaataatgatgaaggagagtggagtggcccaccacctgaatgcagaggaaaatct s_at ctaacttccaaggtcccaccaacagttcagaaacctaccacagtaaatgaccaactacagaagtctcaccaacttctcag aaaaccaccacaaaaaccaccacaccaaatgctcaagcaacacggagtacacctgatccaggacaaccaagcattac atgaaacaaccccaaataaaggaagtggaaccacttcaggtactacccgtcactatctgggcacacgtgatcacgttga caggatgatgggacgctagtaaccatgggcttgctgacttagccaaagaagagttaagaagaaaatacacacaagtat acagactgacctagtacttagactta 25 202286_ gtatgacaacccgggatcgtagcaagtaactgaatccattgcgacattgtgaaggcttaaatgagatagatgggaaata s_at gcgagttatcgccagggataaattatttgatgagaccacttgtatcatggcctacccgaggagaagaggagtagttaac tgggcctatgtagtagcctcatttaccatcgtagtattactgaccacatatgatgtcactgggaaagaagcctgatcagct gcctgaacgcagtaggatgtattgaggacagacattgcccggaaactcagtctatttattatcagcttgccc 26 202310_ tggcctacatggaccagcagactggcaacctcaagaaggccctgctcctccagggctccaacgagatcgagatccgc s_at gccgagggcaacagccgcttcacctacagcgtcactgtcgatggctgcacgagtcacaccggagcctggggcaaga cagtgattgaatacaaaaccaccaagacctcccgcctgcccatcatcgatgtggcccccaggacgaggtgccccaga ccaggaattcggcttcgacgaggccctgtctgatcctgtaaactccctccatcccaacctggctccctcccacccaacc aactttccccccaacccggaaacagacaagcaacccaaactgaaccccctcaaaagccaaaaaatgggagacaatttc acatggactaggaaaatattatttcattgcattcatctctcaaacttagatttatattgaccaaccgaacatgacca 27 202311_ gctccccattatataccaaaggtgctacatctatgtgatgggtggggtggggagggaatcactggtgctatagaaattga s_at gatgcccccccaggccagcaaatgaccatttgacaaagtctattatattccagatattattntantattattattagtgga tggggacttgtgaatttactaaaggtgctatttaacatgggaggagagcgtgtgcggctccagcccagcccgctgctca catccaccctctctccacctgcctctggatctcaggcctctgctctccgacctctctcctctgaaaccctcctccacagct gcagcccatcctcccggctccctcctagtctgtcctgcgtcctctgtccccgggtttcagagacaacttcccaaagcacaa agcagtattncccctaggggtgggaggaagcaaaagactctgtacctattagt 28 202403_ aacctgaaaacatcccagccaagaactggtataggagctccaaggacaagaaacacgtctggctaggagaaactatca s_at atgctggcagccagatgaatataatgtagaaggagtgacttccaaggaaatggctacccaacttgcatcatgcgcctgc tggccaactatgcctctcagaacatcacctaccactgcaagaacagcattgcatacatggatgaggagactggcaacct gaaaaaggctgtcattctacagggctctaatgatgagaacttgagctgagggcaacagcaggacacttacactgactt gtagatggctgctctaaaaagacaaatgaatggggaaagacaatcattgaatacaaaacaaataagccatcacgcctgc ccaccttgatattgcaccatggacatcggtggtgctgaccaggaattctagtggacattggcccagtctga 29 202404_ actacccatgagtgtgatccacattgttaggtgctgacctagacagagatgaactgaggtccttgattgattgacataata s_at caaaggtgctaattaatagtatttcagatacttgaagaatgagatggtgctagaagaatttgagaagaaatactcctgtatt gagagtatcgtgtggtgtattattaaaaaatttgatttagcattcatattaccatcttattcccaattaaaagtatgcagattatt tgcccaaagagtcctatatcagattcagcatttgactagccagtctcattacatatatccatggaccacagaagctag tttcttgggca 30 202431_ gcaacaaccgaaaatgcaccagccccaggtcctcggacaccgaggagaatgtcaagaggcgaacacacaacgtctt s_at ggagcgccagaggaggaacgagctaaaacggagcttattgccctgcgtgaccagatcccggagaggaaaacaatg aaaaggcccccaaggtagttatccttaaaaaagccacagcatacatcctgtccgtccaagcagaggagcaaaagctcat actgaagaggacttgagcggaaacgacgagaacagttgaaacacaaacttgaacagctacggaactcagtgcgtaa ggaaaagtaaggaaaacgattccactaacagaaatgtcctgagcaatcacctatgaacttgatcaaatgcatgatcaaat gcaacctcacaaccttggctgagtc 31 202504_ ggaaacctctcagtgtcttgacatcaccctacccaggcggtgggtctccaccacagccactttgagtctgtggtccctgg at agggtggcactcctgactggcaggatgaccttagccaagatattcctctgaccctctgctgagataaagaattcccttaa catgatataatccacccatgcaaatagctactggcccagctaccatttaccatttgcctacagaatttcattcagtctacactt tggcattctctctggcgatggagtgtggctgggctgaccgcaaaaggtgccttacacactgcccccaccctcagccgag ccccatcagaggctgcctcctccactgattaccccccatgagcatatcaggg 32 202718_ atccccaactgtgacaagcatggcctgtacaacctcaaacagtgcaagatgtctctgaacgggcagcgtggggagtgct at ggtgtgtgaaccccaacaccgggaagctgatccagggagcccccaccatccggggggaccccgagtgtcatctcttct acaatgagcagcaggaggcttgcggggtgcacacccagcggatgcagtagaccgcagccagccggtgcctggcgc ccctgccccccgcccctctccaaacaccggcagaaaacggagagtgcttgggtggtg 33 202779_ ccgaacgtgggcgccaatggcgagatctgcgtcaacgtgctcaagagggactggacggctgagctgggcatccgac s_at acgtactgctgaccatcaagtgcctgctgatccaccctaaccccgagtctgcactcaacgaggaggcgggccgcctgc tcaggagaactacgaggagtatgcggctcgggcccgtctgctcacagagatccacgg 34 202831_ ctacccttatgatgacccattaccctcatgaccgatcccaagctcatcataggagccctgtgcgccgctcagatgtggcc at tggaactagagaagacctcatagggccggagggagagcccaccgacgctacagccgcaccacccaaccatcaaca ttgagcctgacatcaagcgcctccttaaagagccatatagatgtgaactgctcaacacacagatctcctactccatccagt cctgaggagccttaggatgcagcatgcatcaggagacactgctggacctcagcattcccttgatatcagtccccacact gcagagccttgcctttcccctctgcctgtttccttttcctctcccaaccctctggttggtgattcaacttgggctccaagacttg ggtaagctctgggccacacagaatgatggcaccacctaaaccctcatgggtgg 35 202833_ gaagcgataggcatgataacatccagcactgtaagaagctgtccagctgggtactgctaatgaaatacctgggcaatgc s_at caccgccatcacacctacctgatgaggggaaactacagcacctggaaaatgaactcacccacgatatcatcaccaagt tcctggaaaatgaagacagaaggtctgccagcttacatttacccaaactgtccattactggaa 36 202859_ gtacccagttaaattacatttcagataaacaacaaataattattagtataagtacattattgatatctgaaagattaattgaac x_at taacaatcctagatgatactcccagtcagtcattgccagctgtgaggtagtgctgtgagaattacggaataatgagttag aactattaaaacagccaaaactccacagtcaatattagtaatacttgctggagaaacttgatattatgtacaaatagattctt ataatattatttaaatgactgcattataaatacaaggcatatattataacataagatgatttatgtgctctccaaattatatact gtttctgattgtat 37 202935_ gagaggaccaaccagaattccctaggacatagtgatattgattatattagattgattacttatatatatccttaaaga s_at catttaagctaaaggcaactcgtacccaaataccaagacacaaacatgacctatccaagcgcattacccacttgtggcca atcagtggccaggccaaccaggctaaatggagcagcgaaatcaacgagaaactggactattaaaccctcacagagc aagcgtggaggatgatggagaatcgtgtgatcagtgtgctaaatctctctgcctgtaggactagtaattattatttagcagt aattaaagaaaaaagtcctctgtgaggaatattctctatataaatattatagtatgtactgtgtatgattcattaccattagag gggatttatacatattatagataaaattaaatgctcttattatccaacagctaaactactcttagagaacagtgtgccctagct tttcttgcaaccagagta 38 202936_ gtagtgtatcactgagtcatttgcagtgattctgccacagacctagggctgccttatattgtgtgtgtgtgtgggtgtgtgtg s_at tgattgacacaaaaacaatgcaagcatgtgtcatccatatactctacatcactcaggagtgagggaggctacctggagg ggatcagcccactgacagaccttaatcttaattactgctgtggctagagagatgaggattgctattaaaaaagacagcaa acttattattatttaaaaaaagatatattaacagattagaagtcagtagaataaaatcttaaagcactcataatatggcatcct tcaatactgtataaaagcagatctattaaaaaagatacttctgtaacttaagaaacctggcatttaaatcatattagtattag gtaaaagctaggtagtgacgtgattgatgatcacttgatccctcccagccccaaaccattgactctccgtgaaacttac cttt 39 202954_ gccaccctgaatcagacaaccattcaaatgggtagggaccatccatggagcagctggaacagtatatgaagacctgag at gtataagctctcgctagagaccccagtggctacccttacaatgcgcccacagtgaagacctcacgccctgctatcaccc caacgtggacacccagggtaacatatgcctggacatcctgaaggaaaagtggtctgccctgtatgatgtcaggaccatt ctgctctccatccagagccactaggagaacccaacattgatagtcccttgaacacacatgctgccgagctctggaaaaa ccccacagcattaagaagtacctgcaagaaacctactcaaagcaggtcaccagccaggagccctgacccaggctgcc cagcctgtccttgtgtcgtctttttaatttttccttagatggtctgtcctttttgtgattt 40 202998_ gccagtcttgaccgggatgaggcccacagacaggagtcatcagatgtcccattcaagccaccgagctcaccacagac s_at acagtggagccgcgctcactccagtgacacgtggacaaatgcgggctcatcagcccccccagagagggtcaggccg aaccccatactcctcctcttaggtcattacagcaaacttgaatatctagacctctcaccaatgaaaccctccagtctattata gtcacatagataatggtgccacgtgattctgataggtgagctcagacttggtgatccctctccacaacccccacccatg tattcaagatactattattatattacacagacattgaagcacaaatttattggcatttaatattggacatctgggcccaggaa gtacaaatctaaggaaaaaccaacccactgtgtaagtgactcatcacctgagaccaattctgtgggtattgattcaacgg tgctataaccagggtcctgggtgacagggcgctcactgagcaccatgtgtcatcacagaca 41 203083_ caggaaatagtcactcatcccactccacataaggggatagtaagagaagtctgtctgtctgatgatggatagggggcaa at atattaccccatctgttaatagtcatcacatactatgccaaacaggaacgatccataactttagtcttaatgtacacattgca attgataaaattaattagttgatcattgaggagatcgagtgagattgctgcactattacttattgcgtgtggagctgtattc ccgagacaacgaagcgagggatacttcattaaatgtagcgactgtcaacagcgtgcaggattctgatctgtgagtggg gtcaaccgtacaatggtgtgggaatgacgatgatgtgaatatttagaatgtaccatattattgtaaattatttatgatactaaa caaatttatcgtataggagatgaaacgtcatgtgattgccaaagactgtaaatatttatttatgtgacacatggtcaaaatttc accactgaaaccctgcacttagctagaacct 42 203124_ atggtaacatgtatattgccctgggtctgggtgggtccagtcagtctcagatttacaagcatttaggagcctaggtaaaag s_at ctgctagtattcattaaaagttatatttatgacttgcaatgatagaaaactccaccaattaaatggcatatataatattatgtgt gtacttcacagtgttaaaaataccctcatacgttattgcatttgatatcacagaaagtgcatataaccagtactctgggtgc aataaataatatgtagaaatttaagtcctccaattccagcatatccagtgagattgacagtgtgatatgtggaatgataagg atatacaattgtactttatataaattggacttgacacttaaatgtgacatgaaataattgtgctgctacattatactggaaatta acaggggaaaagggaagagctcaggctcccttgaggactgctagtggtgttaggagtggttacaactgagatttagta accatttaaccg 43 203213_ tgctaagttcaagatcgtaatgattgaagtattatatgctctgaatgataaatgactcatcagatcagccatgagttaact at atacaacctggctaaagatgaatatttactactggtatataatattgacctaaatgataagcattcggaatgagaaaactat acagatttgagaaatgatgctaaatttataggagattcagtaacttaaaaagctaacatgagagcatgccaaaatttgctaa gtcttacaaagatcaagggctgtccgcaacagggaagaacagattgaaaatttatgaactatcttattataggtaggattg aaagctattgtctaagtgaattcttatgccaggtcagagtaataactgaaggagntgcttatcaggattcgagtctgagtt taaaactacacattagacatagtgatattagcagccatc 44 203256_ gtggccgtagcaacttggcggagacaggctatgagtctgacgttagagtggagatccttagccatcaggatggagga at atgtgggcagatgacttcagcactgaaaacctctccacctgggccagggagcctcagaggccaagatccagaagcct cttacctgccgtaaaatgctcaaccctgtgtcctgggcctgggcctgctgtgactgacctacagtggactactctctggaa tggaaccttcttaggcctcctggtgcaacttaatttttttttttaatgctatcttcaaaacgttagagaaagttcttcaaaagtgc agcccagagctgctgggcccactggccgtcctgcatactggtaccagaccccaatgcctcccattcggatggatctctg cgtattatactgagtgtgcctaggagccccttattattattaccctgagcgagctatagatg 45 203313_ agagtggtcattcaacactcctccccctactccaccggacctcaaccaggacttcagtggatttcagatctagtggatga s_at gcactcaaacgggctgcagagatggagcttcaggcaaaacttacagcttaacccattacaagcaaaacagactcagaa atgtcatgattgccggggtgaaggcaagagatgaattgcattatatatatattattattaatatttgcacatgggattgctaaa acagatcctgttactgagatgtatcaatggaatacagtcattccaagaactataaacttaaagctactgtagaaacaaag ggattcttattaaatgatcaggtagattattcataatgtgagatggacccaatatcatgtgattattatttcctcccatccctt tattgttattattcagactgtgcaatacttagagaacctatagcatcactcattcccatgtggaacaggatgcccacatactg tctaatta 46 203510_ gaagccaagggttaacccagcaagctacaaagagggtgtgtcacactgaaactcaatagttgagtaggctgagagca at ggaaaatgattataactaaaagctctctgatagtgcagagacttaccagaagacacaaggaattgtactgaagagctatta caatccaaatattgccgatcataaatgtaataagtaatactaattcacagagtattgtaaatggtggatgacaaaagaaaat ctgctctgtggaaagaaagaactgtctctaccagggtcaagagcatgaacgcatcaatagaaagaactcggggaaaca tcccatcaacaggactacacacttgtatatacattcttgagaacactgcaatgtgaaaatcacgtagctatttataaacttgt ccttagattaatgtgtctggacagattgtgggagtaagtgattcactaagaattagatacttgtcactgcctatacctgcagc tgaactgaatggtacttcgtatg 47 203860_ gaagcaggtggaaacatgagcattcagatcaggtacagtgtacaaggtgaatatcttaaccagacttgccgcagaattg at aacaaatttatgctggaaaaagtgactgaggacacaagcagtgactgcgaccccgatgcccggagtggtggtggccg tctctgtcaagcctggagacgcggtagcagaaggtcaagaaatagtgtgattgaagccatgaaaatgcagaatagtatg acagctgggaaaactggcacggtgaaatctgtgcactgtcaagctggagacacagaggagaaggggatctgctcgtg gagctggaatgaaggatttataaccatcagtcatcacccaatttaattagccatttgcatgatgattcacacacaattgattc aagcattatacaggaacacccctgtgcagctacgtttacgtcgtcatttattccacagagtcaagaccaatattctgccaaa aaatcaccaatggaaattacatgatataaatacttgtactatagatgtacactgctgtg 48 203878_ tgccagcgactgtctcagactgggcagggaggctaggcatgacttaagaggaagggcagtcagggacccgctatgc s_at aggtcctggcaaacctggctgccctgtctcatccctgtccctcagggtagcaccatggcaggactgggggaactggagt gtccttgctgtatccctgttgtgaggttccttccaggggctggcactgaagcaagggtgctggggccccatggccttcag ccctggctgagcaactgggctgtagggcagggccacttcctgaggtcaggtcttggtaggtgcctgcatctgtctgcctt ctggctgacaatcctggaaatctgactccagaatccaggccaaaaagttcacagtcaaatggggaggggtattatcatg caggagaccccaggccctggaggctgcaacatacctcaatcctgtcccaggccggatcctcctgaagcccattcgcag cactgctatcctccaaagccattgtaaatgtgtgtacagtgtgtataaaccacttcactt 49 203895_ gactaatccatacacagttaacctaatgccaaataaatactggttaaataaatgtatggcacagaatataatttgactatcaa _at gactatagcataatgaaaaaccctctctctatatatatatgtgtatatgaattatgtgggcattcttgatacttcaagactagat gaaaaaaatacataactaatttaatatacacaaaaatatttatgcagattacagaatttcatatcaggaaatgaccatttatgt ctgttaaatatcaaaacaatttgctacagtgttaatctgcatggtattaagcctgctgtagttgagagcagacagtgcatga aaaagtattccgctgggaattgagccatgccaccaaagccaagaggagcgcatggaaacccggtagtctagaactaat cagattactgatatagggcacagcaccagatgaattgagtatatgatgtaaaaattgattctgtgtgacctctgaacaaa gcgg 50 203896_ gtccagcttgaacatctagaattcctagagaaacagaatgagcaggcgaaggagatgcagcagatggtgaaattggaa s_at gccgagatggaccgcagaccagcaacagtagtatgaaactccaaaatgcaaactgaagcagcaaacccacaaagcat caaaagactcactcacaaaacactgaacacaaactccatggatgaaagctgatattagatcattatgtgtaaacaagat gatatctgaaaccagagagacttggaatgtctgactgacactatttaacagcttgagtattgcatttccaggccaaacaaa aatagctacaaatccacaaaaatttactattccagtaaggcagagtccaaccattgataatacaacttaaacatgatgctat aaaataccatcacaagtaaatgagcaggtgtgaacaactcacctagtgatgccttagg 51 203961_ ggactagagcaacatcgtgctgcccaaaggactaacctatgcaaactagttcacatatagtggatgtcgcagttaatgtgt at aataagacattatacccctgcataatgtacaacagcattgaaatgacacattaagcctagcatcacattgtatagtacagtc actcacaaaccatcaaggctaccctaatcattaacattaatatttgataaaagcaaatcaccgatttatctattgaaactact taaatgacggcaaaccaggaatgacagatggctgtgtcagcaatggattaatgtgaccctgcaagtggtctcctatgan tagaactgcgactcaaatgcactctatcagggtcttaatattctgtgattctctctgtatagtaaaacattataacacattaat acctatctctacacatagg 52 203962_ gtcaaggcattgtatgagatctgtggttattattctgtgatgcttagactacttgaacccataaacttggaagaatattgag s_at caaattactcagagtctgtatgacttcagtatattcctgggaatgccataggattattgtgcttgatacatggtatccagtag catagtatcacactagtaatccagagctgttaagaatgatgtactttaaaggaaaagagaaaactgcatcacagtcccatt ctccagtgtccatgcaatgaattgctgagcatttaggaagcagcaccaagtctattacaggcatggtgtgaaacttgatga tgacctgtgatcaaaattgaaccattgtacagtaggcactgatgcttcaaaatatgtagaattgtggagatgattaatttgc gagactaactagagagtgtaacagattgaagaaaacattgaatgattacaaatgaaggggcttcacggaatgttacaa 53 204051_ aaccagccagtcccaagaagaacattaaaactaggagtgcccagaagagaacaaacccgaaaagagtgtgagctaac s_at tagtaccaaagcggagacttccgacttccttacaggatgaggctgggcattgcctgggacagcctatgtaaggccatgt gcccatgccctaacaactcactgcagtgctatcatagacacatcttgcagcattatcttaaggctatgcttcagatttatt gtaagccatcacaagccatagtggtaggatgccctaggtacagaag 54 204127_ agtgattgtcattagctctgccatataattaaatattaggacatggaccaaagggatacttgacaaatttgtgtgacaga at ctccgaacaattcattactacgaagtataatttataaaataaaatatacccatataagggtacagatgatattgaccagtga aactatgatcccaatcaaggtatagatgccgtcaccccaaaaagaccctccatatccattgcagtcagttcatccctacc ctggcccagatgatcactgatcagtcattatagatgagattgccagttcaagaatttaatggaatcagatattgtaagcatt cagtgtaatacttcattctctctcattattgagattcatccatattgagaatgatcactagttaatgatattgacaatatttagta tatacttttaaagcctattcacttgctgatggatctt 55 204170_ cgctctcgatcattactgcagcgcgccacgaggatggcccacaagcagatctactactcggacaagtacttcgacgaa s_at cactacgagtaccggcatgttatgttacccagagaactaccaaacaagtacctaaaactcatctgatgtctgaagaggag tggaggagacttggtgtccaacagagtctaggctgggacattacatgattcatgagccagaaccacatattatctattag acgacctcaccaaaagatcaacaaaaatgaagatatctggggatcgtcaaatattacaaatttaatgtatatgtgtatata aggtagtattcagtgaatacttgagaaatgtacaaatattcatccatacctgtgcatgagctgtattatcacagcaacaga gctcagttaaatgcaactgcaagtaggttactgtaagatgataagataaaagttcaccagtcagatttctcttaagtgcct 56 204259_ ctcatggggactcctacccatttgatgggccaggaaacacgctggctcatgccatgcgcctgggacaggtctcggagg at agatgctcacttcgatgaggatgaacgctggacggatggtagcagtctagggattaacttcctgtatgctgcaactcatga acttggccattctagggtatgggacattcctctgatcctaatgcagtgatgtatccaacctatggaaatggagatccccaa aatataaactacccaggatgatattaaaggcattcagaaactatatggaaagagaagtaattcaagaaagaaatagaaa cacaggcagaacatccattcattcattcattggattgtatatcattgagcacaatcagaattgataagcactgacctccact ccatttagcaattatgtcacccttattattgcagaggtattgaatgtattcactcatttattggttaaactcattatggtgtga ctgtgtcttattccatctatgagctttgtcagtgcgcgtagatgt 57 204320_ gaaaatgtaccaggtgccaccaacccattagtgccacatgcaagattgaataaggatgtatggaaaacaacgctgcat at atacaggtaccatttaggaaataccgatgcctagtgggggcagaatcacagacaaaagattgaaaatcataaagatata agttggtgtggctaagatggaaacagggctgattcttgattcccaattctcaactctccttttcctatttgaatttctttggtgct gtagaaaacaaaaaaagaaaaatatatattcataaaaaatatggtgctcattctcatccatccaggatgtactaaaacagtg tgataataaattgtaattattagtgtacagactatactgttatctgtgtccataccaaaacttgcacgtgtccctgaattccgc tgactctaatttatgaggatgccgaactctgatggcaataatatatgtattatgaaaatgaagttatgataccgatgacccta agtcc 58 204351_ gggtctgaatctagcaccatgacggaactagagacagccatgggcatgatcatagacgtatacccgatattcgggcag at cgagggcagcacgcagaccctgaccaagggggagctcaaggtgctgatggagaaggagctaccaggcacctgcag agtggaaaagacaaggatgccgtggataaattgctcaaggacctggacgccaatggagatgcccaggtggacttcagt gagttcatcgtgacgtggctgcaatcacgtctgcctgtcacaagtactagagaaggcaggactcaaatgatgccctgga gatgtcacagattcctgcagagccatggtcccaggcacccaaaagtgatgaggcaattattcccctaggctgagcctg ctcatgtacc 59 204401_ gtagctggacccacgaggaggaaccaggctactaccccagtactgaggtggtggacatcgtctctgccactcctgacc at cagccctgaacaaagcacctcaagtgcaaggaccaaagggggccctggcaggagtgggaggcttgctgatggctgc tggaggggacgctggctaaagtgggtaggccttggcccacctgaggccccaggtgggaacatggtcacccccactct gcataccctcatcaaaaacactctcactatgctgctatggacgacctccagctctcagttacaagtgcaggcgactggag gcaggactcctgggtccctgggaaagagggtactaggggcccggatccaggattctgggaggcttcagttaccgctgg ccgagctgaagaactgggtatgaggctggggcggggctggaggtggcgccccctggtgggacaacaaagaggaca ccatttttccagagctgc 60 204404_ agaccaagacataccggcagatcaggttaaatgagttattaaaggaacattcaagcacagctaatattattgtcatgagtct at cccagagcacgaaaaggtgctgtgtctagtgctctctacatggcatggttagaagctctatctaaggacctaccaccaat cctcctagttcgtgggaatcatcagagtgtccttaccactattcataaatgactatacagtggacagccctccagaatggt acttcagtgcctagtgtagtaacctgaaatatcaatgacacattaacatcacaatggcgaatggtgactatattcacgatt tcattaatttgaaagcacacaggaaagcttgctccattgataacgtgtatggagacttcggattagtcaattccatatc 61 204470_ tatgattaactctacctgcacactgtcctattatattcattctattgaaatgtcaaccccaagttagttcaatctggattcatattt at aatttgaaggtagaatgattcaaatgactccagtcattatgttaatatactgaggagcctgcaacatgccagccactgtga tagaggctggcggatccaagcaaatggccaatgagatcattgtgaaggcaggggaatgtatgtgcacatctgattgtaa ctgatagatgaatgtcagagttatttattgaaatgatttcacagtgtgtggtcaacatactcatgagaaactttaagaactaa aatgactaaatatcccaggacatatatgtattcagtaaggcatactgccttgataatggtagattacagtgatctggctta gaaca 62 204475_ gaagaactgtctattactcagtcattataacctctagagtcactgatacacagaatataatcttatttatacctcagtagcata at attatactatttagaatgtagccattagtactgatataatttagaccacaaatggtgggtacaaaaagtcaagtagtggctt atggattcatataggccagagagcaaagatcattccagagtatgcaactctgacgttgatcccagagagcagcttcagt gacaaacatatcattcaagacagaaagagacaggagacatgagtattgccggaggaaaagcagctcaagaacacat gtgcagtcactggtgtcaccctggataggcaagggataactcactaacaca 63 204580_ agatgatggaccctggttatcccaaactgattaccaagaacttccaaggaatcgggcctaaaattgatgcagtcactattc at taaaaacaaatactactatttcaccaaggatctaaccaatttgaatatgacttcctactccaacgtatcaccaaaacactgaa aagcaatagctggtaggagttagaaatggtgtaattaatggatagttagttcacttcagcttaataagtatttattgcatattt gctatgtcctcagtgtaccactacttagagatatgtatcataaaaataaaatctgtaaaccataggtaatgattatataaaata cataatattatcaattagaaaactctaattgtccattcagcttgactctactattaagatgaaaatagttaccacaaagcaag ataattctatttgaagcatgctctgtaagttgatcctaacatccaggactgagaaattatacttacactggcataactaaa 64 204620_ tgccgtgctcccaaaacatataaatgaaagtattggcattcaaaaagacagcagacaaaatgaaagaaaatgagagca s_at gaaagtaagcataccagcctatctaatttcatagattctatttgcctccagtgcagtccatacctaatgtataccagcctact gtactatttaaaatgctcaatttcagcaccgatggccatgtaaataagatgatttaatgagatataatcctgtatataaaataa aaagtcacaatgagtagggcatatttaatgatgattatggagccttagaggtattaatcattggacggctgatttatgtag ataggctggaaatggatcacttgctattgactgtcagcaagactgaagatggcattcctggacagctagaaaacacaa aatcagtaggtcattgcacctatctcagccataggtgcagatgatctacatgatgctaaaggctgcgaatgggatcctga tggaactaaggactccaatgtcgaactcactagctgc 65 204702_ tgctctccagtgtacccatgatggaagtatcttgatagtacccaaagaactggtggcctcaggccacaaaaaggaaacc s_at caaaagggaaagagaaagtgagaagaaactgaagatggactctattatgtgaagtagtaatgacagaaactgattatttg gatcagaaaccattgaaactgcttcaagaattgtatattaagtactgctacttgaataactcagttaacgctgattgaagctt acatggacaaatgataggacttcaagatcacacttgtgggcaatctgggggagccacaactatcatgaagtgcattgtat acaaaattcatagttatgtccaaagaataggttaacatgaaaacccagtaagactaccatcaggcagccatccatttaag agtaagaggttacttcaaaaagagcaaacactggggatcaaattatataagaggtatttcagattaaatgcaaaatagcc ttattacatttagtagttagcactatagtgagcattcaaacactatataatc 66 204855_ cacgttcgcagagcattcagattgtggaatgaggataaggaattatagacctctagtagctgaaatgcaagaccccaag at aggaagttcagatcttaatataaattcactacatattgatagctgtcccatctggtcatgtggaggcactagactggtggca ggggcactagctgactcgcacagggattctcacaatagccgatatcagaatagtgagaaggaacttgtctatcatctaa tatgatagcgggaaaaggagaggaaactactgccatagaaaatataagtaaagtgattaaagtgctcacgttaccttgac acatagtattcagtctatgggatagttactttagatggcaagcatgtaacttatattaatagtaatagtaaagagggtggat aagctatccctgagccggacatggattacactctataaaaaatatatatttaccaaaaaattagtgacattcatctcccatc tcttccttgacatgcattgtaaataggttcttcttgttctgag 67 204885_ taccagaacatgaacgggtccgaatacttcgtgaagatccagtccacctgggtggggcccccacggaggatttgaag s_at gcgctcagtcagcagaatgtgagcatggacttggccacgttcatgaagctgcggacggatgcggtgctgccgttgactg tggctgaggt 68 205174_ gtctggcacaccatggatgacaatgaagaaaataggatgaatcaaccattgacaatctaaacaaaatcctacaagtatt s_at gtgaggaatatcacatagtaatactctgatttagataggataattggactagaattgaattcaaaagtcaaggcatcattta aaataatctgatttcagacaaatgctgtgtggaaacatctatcctatagatcatcctattcttatgtgtctaggttatcagatca attacagaataattgtgagtgatattgtgtcctaaattgctcattaattatatttacagattgaaaaagaggcaccgtgtaaag aaaatggcaaaataaatatctaccaaggatcatcatcacgatagctaaacagtacttaaatagcggaggaactaggtag cattcgaatatatgattattcatatgtggaaatctattacatgtaatacaaaacaaacatgtagatgaaggcggtcagattt ctttgag 69 205361_ aaggcggctgcagaagatgtcaatgttactacgaagatcaacaaaagataaacaaatttgcacggaatacaagtagaat s_at cacagagctgaaggaagaaatagaagtaaaaaagaaacaactccaaaacctagaagatgcagtgatgacatcatgctt gcagatgatgattgcttaatgataccttatcaaattggtgatgtcacattagccattctcaagaagaaacgcaagaaatga agaagaagcaaagaaaaatttgcaagaagaaattgacgccttagaatccagagtggaatcaattcagcgagtgttagca gatttgaaagttcagttgtatgcaaaattcgggagcaacataaaccttgaagctg 70 205366_ cctcagcctgatcaggcacctggtgagaactgaggagcggactcacttgatgatcctggaagcagagcaaaagactc s_at ttgtccctgtcgcgtctcattagtccatgtcccccgtgcacggttcaatggtagattcgctgtcctcagcgggggccttgaa gactccctgatcccagacctggtcgtctctcccaccccctccccaaagccactggaaggagcacatactacctagaagt aagaagaggagcctcagaagaaaacaaagactatatattaattactatgtgagtgatgtagtcagtcttagctctggac g 71 205470_ gccaacatcaccatcattgagcaccagaagtgtgagaacgcctaccccggcaacatcacagacaccatggtgtgtgcc s_at agcgtgcaggaagggggcaaggactcctgccagggtgactccgggggccctctggtctgtaaccagtctcttcaagg cattatctcctggggccaggatccgtgtgcgatcacccgaaagcctggtgtctacacgaaagtctgcaaatatgtggact ggatccaggagacgatgaagaacaattagactggacccacccaccacagcccatcaccctccataccacttggtgatg gacctgacactctgttaataagaaaccctaagccaagaccctctacgaacattctagggcctcctggactacaggagat gctgtcacttaataatcaacctggggacgaaatcagtgagacctggattcaaattctgccttgaaatattgtgactctggga atgacaacacctggatgactctgagtatccccagccccaaagacagctcctggccatatatca 72 205476_ ttcacacggcagctggccaatgaaggctgtgacatcaatgctatcatattcacacaaagaaaaagagtctgtgtgcgca at aatccaaaacagacttgggtgaaatatattgtgcgtctcctcagtaaaaaagtcaagaacatgtaaaaactgtggcttttct ggaatggaattggacatagcccaagaacagaaagaaccagctggggaggaggatcacttgcacatcatggagggat agtgcttatctaatagtgcctcactggacttgtccaattaatgaagttgattcatattgcatcatagtagctagataagcatc acattaaagttaaactgtatatatgttatttatagctgtaggattctgtgatagctatttaatactaattaccataagctattagg atagtgcaaagtataaaattatatagggggggaataagattatatggactacttgcaagcaacaa 73 205479_ cccgaccggtgggcatagtgaggcccatggagagaaatgaataatttcccaattaggaagtgtaagcagctgaggtct s_at cttgagggagcttagccaatgtgggagcagcggtaggggagcagagacactaacgacttcagggcagggctctgata accatgaatgtatcaggaaatatatatgtgtgtgtatgatgcacacttgagtgtgggctgtgagtgtaagtgtgagtaaga gctggtgtctgattgttaagtctaaatataccttaaactgtgtggactgtgatgccacacagagtggtattctggagaggtt ataggtcactcctggggcctcagggtcccccacgtgacagtgcctgggaatgtacttattctgcagcatgacctgtgacc agcactgtctcagatcactacacatagatgtccattcaggccagttatccatccattagcctagttcatccaatcctcact gggtgggg 74 205513_ aacaaagactcacttgcgtctctgcttcaggtaacttcaacatctccgctgatgagcctataactgtgacacctcctgactc at acaatcatatatctccgtcaattactctgtgagaatcaatgaaacatatttcaccaatgtcactgtgctaaatggactgtcttc ctcagtgtgatggagaaagcccagaaaatgaatgatactatataggatcacaatggaggagcgctcatgggggcccta tatcacctgtattcagggcctatgtgccaacaataatgacagaacctactgggaacttctgagtggaggcgaaccactga gccaaggagctggtagttacgagtccgcaatggagaaaacttggaggacgctggagcaaatactaataagcccaaac tacctcagctgcataaaatccatttgcagtggagaccatgatattgtccttatgccact 75 205713_ caaacgtattggcaggcgaacccatccgtgctgtggccgagcctggcatccaactcaaggctgtgaagtatccacag s_at gccccggggaacagctgcggaacgctctgtggcatacaggagacacagagtcccaggtgcggctgctgtggaagga cccgcgaaacgtgggaggaaggacaagaagtcctatcgaggacctgcagcaccggccccaagtgggctacatcag ggtgcgattctatgagggccctgagctggtggccgacagcaacgtggtcaggacacaaccatgcggggtggccgcct gggggtcactgatctcccaggagaacatcatctgggccaacctgcgttaccgctgcaatgacaccatcccagaggact atgagacccatcagctgcggcaagcctagggacc 76 205765_ caccacctacctatgatgccgtggtacagatggagtaccttgacatggtggtgaatgaaacactcagattattcccagag at ctattagacttgagaggacttgcaagaaagatgagaaatcaatggggtattcattcccaaagggtcaatggtggtgattcc aacttatgctatcaccatgacccaaagtactggacagagcctgaggagaccgccctgaaaggacagtaagaagaag gacagcatagatccttacatatacacaccctaggaactggacccagaaactgcattggcatgaggatgctctcatgaac atgaaacttgctctaatcagagtcatcagaacactcatcaaaccagtaaagaaacacagatccccttgaaattagacac gcaaggacttatcaaccagaaaaacccattgactaaaggtggattcaagagatggaaccctaagtggagaatgagtta actaaggacactactaggtatcaagaaagctgtgccccagaacaccagagatttcaacttagtca 77 205815_ tgctatgccttgatagtcaccaaaatcctggacagatgcagatctggcctgccagaagcggccctctggaaacctggtg at tctgtgctcagtggggctgagggatcatcgtgtcctccctggtgaagagcattggtaacagctactcatacgtctggattg ggctccatgaccccacacagggcaccgagcccaatggagaaggagggagtggagtagcagtgatgtgatgaattact ttgcatgggagagaaatccctccaccatctcaagccccggccactgtgcgagcctgtcgagaagcacagcatttctgag gtggaaagattataactgtaatgtgaggttaccctatgtctgcaagttcactgactagtgcaggagggaagtcagcagcct gtgtaggtgtgcaactcatcatgggcatgagaccagtgtgaggactcaccctggaagagaatattcgcttaattccccca acctgaccacctcattcttatattcactgatcacctccccgctgtcatttcagtctatcattagtc 78 205825_ taccattcccaatctagtgctagatgtataaatattcattgattcacctaacaaaatattactgggttaaaaccccagccaa at ctcattgggagtagccaaaggacactctcaagaagattaatatttaaataaaatcatattgaatgatccaacctggagtat aatattcagatataaaacagttttgtcagtctttcttagtgcctgtgtggatttttgtgaaaatgtcaaagagaaaacttatatac tatacccttgaaatataaactatattactttacaggtatttataatataccaatgatttatcaaacagaatataaagagcataa taaattatattaaagaaccaaaagattcctgagaataagaaagatcacccaataaaatatattgaaaggcatgacctctgt caatgaaaaaaagtacatgtatgtgagtgatattaaaagtgacatagtctaatagcctaatacaacatgtagctgagataa catgtgtggtcttg 79 205828_ gaaaatcgatgcagccatttctgataaggaaaagaacaaaacatatttctttgtagaggacaaatactggagatttgatga at gaagagaaattccatggagccaggctacccaagcaaatagctgaagactaccagggattgactcaaagattgatgctg tattgaagaatagggactatatttattactggatatcacagaggagatgacccaaatgcaaagaaagtgacacacact ttgaagagtaacagctggcttaattgagaaagagatatgtagaaggcacaatatgggcactttaaatgaagctaataattc ttcacctaagtctctgtgaattgaaatgacgattctcctgcctgtgctgtgactcgagtcacactcaagggaacttgagcgt gaatctgtatcttgccggtcattatatgttattacagggcattcaaatgggctgctgcttagcttgcaccagtcacatagagt gatctacccaagagaaggggaagcactcgtgtgcaacagac 80 205886_ cacccaggcggagggtgccacgtggcctcactgattaaggagagtagcactgatgacagcaatgtctggattggcctc at catgacccaaaaaagaaccgccgctggcactggagtagtgggtccctggtctcctacaagtcctgggacactggatcc ccgagcagtgctaatgctggctactgtgcaagcctgacttcatgctcaggattcaagaaatggaaggatgaatcagtga gaagaagactcattgatgcaagttcaaaaactagaggaagctgaaaaatggatgtctagaactggtcctgcaattacta tgaagtcaaaaattaaactagactatgtctccaactcagttcagaccatctcctccctaatgagtagcatcgctgatatcag taccttc 81 205890_ gatcttaaagccacggagaagcctctcatcttatggcattgacaaagagaagaccatccaccttaccctgaaagtggtga s_at agcccagtgatgaggagctgcccttgatcagtggagtcaggtgatgaggcaaagaggcacctcctccaggtgcgaag gtccagctcagtggcacaagtgaaagcaatgatcgagactaagacgggtataatccctgagacccagattgtgacttgc aatggaaagagactggaagatgggaagatgatggcagattacggcatcagaaagggcaacttactcacctggcatctt attgtattggagggtgaccaccctggggatggggtgaggcaggggtcaaaaagcttatttcattaatctcttactcaacg aacacatcactgatgatacccaaaattaatgagaatgagatgagtagagtaagatagggtgggatgggtaggatgaag tatattgcccaactctatgtttctttga 82 205910_ gactccaaggaagctcagatgcctgcagtcattaggttttagcgtcccatgagccttggtatcaagaggccacaagagtg s_at ggaccccaggggctc 83 205927_ tccacacacggccaggcctgatatctacactgctgcccactcctctctccagctccacatgctgtacctggatcattctga s_at agcaaattccgagcattacatcattagtccataaatatactaacatccttaaatatacaatcggaattcaagcatctcccatt gtcccacaaatgtaggctgatagtagaggattgatgtattaggattcaagcaaggcccatatattgcatttatttgaaatgt ctgtaagtctctaccatctacagagatagcacatttgaacgagctggagaaatcccgaggtgtcatttgacatggactct gaacttatctacctataaaatggtagttagatctggaggtctgattagtggcaaaaatacttcctaggtggtgctgggtactt cttgagcatcctgtcaggaggcagataatgctggtgcctctctattggtaatgttaagactgctgggtgggtaggagactt ggc 84 205941_ atactattatcataccacgtgcatgtgaaagggactcatgtagggtaggcctgtataagaatggcacccctgtaatgtaca s_at cctatgatgaatacaccaaaggctacctggatcaggcttcagggagtgccatcatcgatctcacagaaaatgaccaggt gtggctccagatcccaatgccgagtcaaatggcctatactcctctgagtatgtccactcctctactcaggattcctagtgg ctccaatgtgagtacaccccacagagctaatctaaatcagtgctagaaaaagcattctctaactctaccccaccctacaaa atgcatatggaggtaggctgaaaagaatgtaattatattactgaaatacagatttgagctatcagaccaacaaaccaccc cctgaaaagtgagcagcaacgtaaaaacgtatgtgaagcctctcttgaa 85 205983_ gccgaccatctggatcacatcaaggaggtggcaggagccagagccgtgggattggtggggactagatggtgaccaa at gggtccctgaggggctggaggacgtctccaagtatccagacctgatcgctgagctgctcaggaggaactggacggag gcggaggtcaagggcgcactggctgacaacctgctgagggtatcgaggctgtggaacaggccagcaacctcacaca ggctcccgaggaggagcccatcccgctggaccagctgggtggctcctgcaggacccattacggctactcctctgggg caccagcctccatcgccactgggggctcctgctggcctccctcgctcccctggtcctctgtctgtctctcctgtgaaacct gggagaccagagtcccattagggacccggagctccgggaagacccgcccatcccaggactccagatgccaggag ccctgctgcccacatgcaaggaccagcatctcctgagaggacgcctgggcttacctggggggcaggatgcctgggga cagttcag 86 206224_ ggaggataggataatcccgggtggcatctataacgcagacctcaatgatgagtgggtacagcgtgccatcacttcgcc at atcagcgagtataacaaggccaccaaagatgactactacagacgtccgctgcgggtactaagagccaggcaacagac cgttgggggggtgaattacttatcgacgtagaggtgggccgaaccatatgtaccaagtcccagcccaacttggacacct gtgcatccatgaacagccagaactgcagaagaaacagttgtgctattcgagatctacgaagttccctgggagaacaga aggtccctggtgaaatccaggtgtcaagaatcctagggatctgtgccag 87 206239_ gagacgtggtaagtgcggtgcagttttcaactgacctctggacgcagaacttcagccatgaaggtaacaggcatattctt s_at ctcagtgccttggccctgttgagtctatctggtaacactggagctgactccctgggaagagaggccaaatgttacaatga acttaatggatgcaccaagatatatgaccctgtctgtgggactgatggaaatacttatcccaatgaatgcgtgttatgttttg aaggtcggaaacgccagacttctatcctcattcaaaaatctgggccttgctgagaaccaaggttttgaaatcccatcaggt caccgc 88 206286_ gtggaccttagaatacagttttgagtagagttgatcaaaatcaattaaaatagtctattaaaaggaaagaaaacatattaa s_at ggggaggaaccagagtgctgaaggaatggaagtccatctgcgtgtgtgcagggagactgggtaggaaagaggaagc aaatagaagagagaggttgaaaaacaaaatgggttacttgattggtgattaggtggtggtagagaagcaagtaaaaagg ctaaatggaagggcaagtttccatcatctatagaaagctatataagacaagaactcccattattcccaaaggcattataaa aagaatgaagcctccttagaaaaaaaattatacctcaatgtccccaacaagattgcttaataaattgtgtttcctccaagcta ttcaattatttaactgttgtagaagacaaaatgttcacaatatatttagttgtaaaccaagtgatcaaactacatattgtaaagc ccattttt 89 206976_ aagtctgtagtattatgatcctaaaagggaaaattgccttggtaactttcagattcctgtggaattgtgaattcatactaagct s_at ttctgtgcagtctcaccatttgcatcactgaggatgaaactgacttngtatttggagaaaaaaaactgtactgttgttcaag agggctgtgattaaaatattaagcatttgttcctgccaaggtagttttcttgcattttgctctccattcagcatgtgtgtgggtg tggatgtttataaacaagactaagtctgacttcataagggctttctaaaaccatttctgtccaagagaaaatgactttttgatt gatattaaaaattcaatgagtaaaacaaaagctagtcaaatgtgttagcagcatgcagaacaaaaactttaaactttctctct cactatacagtatattgtcaatgtgaaagtgtggaatggaagaaatgtcgatcctgttgtaactga 90 207158_ gcaccctggtgtgactctagtgatctacgtagctcggatttttggcacatggatcaacaaaatcggcaaggtctcaggga at catgttaacagtggagtaactattcagattatgagagcatcagagtattatcactgctggaggaattngtcaactacccac ctggggatgaagctcactggccacaatacccacctctgtggatgatgttgtacgcactggagctgcactgcataattctaa gtatccaccctgtttaaagatttcaagaagatggcaaaatcatcttacatattcagacttcatatcaaaactgccattacca aacgattccgccacacatcatttagctacagggctgatacatcatctgtggcttggagatgaataggatgattccgtgtgt gtactgattcaagaacaagcaatgatgacccactaaagagtgaatgccatttagaatctagaaatgttcacaaggtacccc aaaactctgtagct 91 207173_ gaacatccaagtattatcttnttaagttgtcaaagaagatccacaaaattagaaaggacaacagttctgagctgtaatttc x_at gccttaaactctggacactctatatgtagtgcatttttaaacttgaaatatataatattcagccagcttaaacccatacaatgta tgtacaatacaatgtacaattatgtctcttgagcatcaatcttgttactgctgattatgtaaatattttgatctactttcatctta aactaatacgtgccagatataactgtcttgtttcagtgagagacgccctatttctatgtcatttttaatgtatctatttgtacaattt taaagttcttattttagtatacatataaatatcagtattctgacatgtaagaaaatgttacggcatcacacttatatttta 92 207457_ aaccgaatgcggtgctacaactgtggtggaagccccagcagttcttgcaaagaggccgtgaccacctgtggcgaggg s_at cagaccccagccaggcctggaacagatcaagctacctggaaaccccccagtgaccttgattcaccaacatccagcctg cgtcgcagcccatcattgcaatcaagtggagacagagtcggtgggagacgtgacttatccagcccacagggactgcta cctgggagacctgtgcaacagcgccgtggcaagccatgtggcccctgcaggcattttggctgcagcagctaccgccct gacctgtctcttgccaggactgtggagcggatagggggagtaggagtagagaagggaacaagggagcaagggaac aagggacatctgaacatct 93 207850_ agaacagcagctttctagggacagctggaaagggacttaatgtgtttgactatttcttacgagggttctacttatttatgtattt at atttttgaaagatgtattttaatattttacatgctgttatttaaagatgtgagtgtgtttcatcaaacatagctcagtcctgattatt taattggaatatgatgggttttaaatgtgtcattaaactaatatttagtgggagaccataatgtgtcagccaccttgataaatg acagggtggggaactggagggtngggggattgaaatgcaagcaattagtggatcactgttagggtaagggaatgtatg tacacatctattattatacttnttnttaaaaaagaatgtcagttgttatttattcaaattatctcacattatgtgttcaacattntat gctgaagtttcccttagacattttatgtcttgcttgtagggcataatgccttgtttaatgtccattctgcagcgttt 94 208079_ ccctcaatctagaacgctacacaagaaatattttgatttactcagcaggtgtgccttaacctccctattcagaaagctccac s_at atcaataaacatgacactctgaagtgaaagtagccacgagaattgtgctacttatactggaacataatctggaggcaaggt tcgactgcagtcgaaccagcctccagattatgaaccagtataagtagcacaattctcgtggctactacacttcagagtgtc atgatattgatgtggagctactgaatagggaggttaaggcacacctgctgagtaaaacaaatatacttgtgtagcgactt aggaatctggtgtctgtccggccccggtaggcctgagggtactagtcctccttaccatcatctccatatgagagtgtgaa aataggaacacgtgctctacctccatttagggatttgatgggatacagaagaggccatgtgtctcagagctgttaagggc ttatttttttaaaacattggagtcatagcatgtgtgtaa 95 208712_ gattgggtatgataatctgttatgtactagtgactgatgttattgattgttaattacaccataatgctaatttaaagagactcc at aaatctcaatgaagccagctcacagtgctgtgtgccccggtcatctagcaagctgccgaaccaaaagaatttgcacccc gctgcgggcccacgtggaggggccctgccctggcagggtcatcctgtgctcggaggccatctcgggcacaggccca ccccgccccacccctccagaacacggctcacgcttacctcaaccatcctggctgcggcgtctgtctgaaccacgcggg ggccttgagggacgctagtctgtcgtgatggggcaagggcacaagtcctggatgagtgtgtatcgagaggccaaagg ctggtggcaagtgcacggggcacagcggagtctgtcctgtgacgcgcaagtctgagggtctgggcggcg 96 209218_ gattccctgcatcaactaagaaaagcctgattattatttcaaacttggtggcgaatgtgagcgggtcctgagggctgatt at ctgtattgtctcctaaccctctagattaattggacacttattgctgagcaatctatgccgtgtatattgattaagtcagaacc aggattacaaaacctcgagcccactcagtagtggtgctgtattgtacaaagcgtgactgtaatatacctctaatttactca gaaatgaagtatatggacattaagcttaaaggggaaccatagtgaatgaatataggaacttaccaagtcctaagagactt ttggaagaggatatatatagcatagtaccataccacttata 97 209309_ tgcggaaatacctgaaatacagcaaaaatatcctggaccggcaagatcctccctctgtggtggtcaccagccaccaggc at cccaggagaaaagaagaaactgaagtgcctggcctacgacactacccagggaaaattgatgtgcactggactcgggc cggcgaggtgcaggagcctgagttacggggagatgacttcacaatggaaatggcacttaccagtcctgggtggtggtg gcagtgcccccgcaggacacagccccctactcctgccacgtgcagcacagcagcctggcccagcccctcgtggtgcc ctgggaggccagctaggaagcaagggaggaggcaatgtgggatctcagacccagtagctgccatcctgcctgatgt gggagctgaaccacagaaatcacagtcaatggatccacaaggcctgaggagcagtgtggggggacagacaggaggt ggataggagaccgaagactgggatgcctgtcttgagtagacttggacccaaaaaatcatctcaccttgagccca 98 209369_ gaagacttactgaggccatagttaattgtgtgaggaacacgccggccatttagccgaaagactgcatcgagccttgaag at ggtattggaactgatgagatactctgaaccgaataatggtgtccagatcagaaattgaccattggacattcgaacagagtt caagaagcattatggctattccctatattcagcaattaaatcggatacactggagactatgaaatcacactcttaaaaatctg tggtggagatgactgaaccaagaagataatctccaaaggtccacgatgggcttaccaacagctccaccttacttcactca tactatttaagagaacaagcaaatataaacagcaacttgtgacctaacagg 99 209752_ agagattcattgcagctcagcatggctcagaccagctcatacttcatgctgatctcctgcctgatgatctgtctcagagcca at aggccaagaggcccagacagagttgccccaggcccggatcagctgcccagaaggcaccaatgcctatcgctcctact gctactactttaatgaagaccgcgagacctgggagatgcagatctctattgccagaacatgaattcgggcaacctggtgt ctgtgctcacccaggccgagggtgcctagtggcctcactgattaaggagagtggcactgatgacttcaatgtctggattg gcctccatgaccccaaaaagaaccgccgctggcactggagcagtgggtccctggtctcctacaagtcctggggcattg gagccccaagcagtgttaatcctggctactgtgtgagcctgacctcaagcacaggattccagaaatggaaggatgtgcc agtgaagacaagactcct 100 209773_ attaccaggatgctgacactaaatgaactgaagatgtgcccttacttggctgattattattccatctcataagaaaaatcag s_at ctgaagtgttaccaactagccacaccatgaattgtccgtaatgacattaacagcatattaaaactgtgtagctacctcaca accagtcctgtctgatatagtgctggtagtatcaccattgccagaaggcctggctggctgtgacttaccatagcagtgac aatggcagtcaggattaaagtgaggggtgaccattagtgagcttagcacagcgggattaaacagtcattaaccagca cagccagttaaaagatgcagcctcactgcttcaacgcagatt 101 209774_ agagagacacagctgcagaggccacctggattgcgcctaatgtgatgagcatcacttaggagaagtcactatttatttatt x_at tatttatttatttatttgatgattagaagattctatgttaatatatatgtgtaaaataaggttatgattgaatctacttgcacactct cccattatatttattgatatataggtcaaacccaagttagttcaatcctgattcatatttaatttgaagatagaaggatgcagat attctctagtcatagttaatatacttcgtgatgacatatcacatgtcagccactgtgatagaggctgaggaatccaagaaaa tggccagtaagatcaatgtgacggcagggaaatgtatgtgtgtctattagtaactgtaaagatgaatgtcagagttatttatt gaaatgatttcacagtgtgtggtcaacatactcatgagaagattaagaactaaaatgactaaatatcccaggacatatat gtattcagtaagatactgccttgataatgttaattatgcagtgatccctc 102 209792_ tcctctcgtggggtgatacccctgtggctctgcccagcatccagctgtctacacccagatctgcaaatacatgtcctggat s_at caataaagtcatacgctccaactgatccagatgctacgctccagctgatccagatgttatgctcctgctgatccagatgcc cagaggctccatcgtccatcctcacctccccagtcggctgaactctccccagtctgcactgacaaacctctgccgccct ccacacctctaaacatctcccctctcacctcattcccccacctatccccattctctgcctgtactgaagctgaaatgcagga agtggtggcaaaggatattccagagaagccaggaagccggtcatcacccagcctctgagagcagttactggggtcac ccaacctgacttcctctgccactccccgctgtgtgactagggcaagccaagtgccctctctgaacctcagtacctcatct gcaaaatgggaacaatgacgtgcctacctcttagacatgttgtg 103 209875_ gaatggtgcatacaaggccatccccgagcccaggacctgaacgcgccactgattgggacagccgtgggaaggaca s_at gttatgaaacgagtcagctggatgaccagagtgctgaaacccacagccacaagcagtccagattatataagcggaaag ctaatgatgagagcaatgagcattccgatgtgattgatagtcaggaactaccaaagtcagccgtgaattccacagccatg aatttcacagccatgaagatatgctggagtagaccccaaaagtaaggaagaagataaacacctgaaatttcgtatactca tgaattagatagtgcatcactgaggtcaattaaaaggagaaaaaatacaatactcactagcatttagtcaaaagaaaaaa tgattatagcaaaatgaaagagaacatgaaatgatctactcagatattggagaatgtgtatctatttgagtctggaaataa ctgatgtgtttgataattagtttagtttgtggcttcatggaa 104 209955_ acagctaccaaggtgacaaactcctctatgcagtgtatcgaaagctgggtgatatgaagttgaagaccagattacagct s_at gtcagaaaattcatagaaatgggatcattgatgaaaaaagaatagccatatggggctggtcctatggaggatacgatcat cactggccatgcatctggaactggtcattcaaatgtggtatagcagtggctccagtctccagctgggaatattacgcgtc tgtctacacagagagattcatgggtctcccaacaaaggatgataatcttgagcactataagaattcaactgtgatggcaag agcagaatatttcagaaatgtagactatcactcatccacggaacagcagatgataatgtgcactacagaactcagcaca gattgctaaagctctggttaatgcacaagtggataccaggcaatgtggtactctgaccagaaccacggcttatccggcct gtccacgaaccacttatacacccacatgacccacttcctaaagcagtg 105 210052_ agtcaagtgaccagcctctgactgtgcctgtatctcccaaattctccactcgattccactgctaaactcagctgtgagctgc s_at ggataccgcccggcaatgggacctgctcttaacctcaaacctaggaccgtcttgctagtcattgggcatggagagaacc catactccagactatacctacccgtgcctgagaaagcatacttgacaactgtggactccagattgagagaattgattctt acattactaaggctaataatgagatgtaactcatgaatgtctcgattagactccatgtagttacttcattaaaccatcagccg gccattatatgggtatcactctgactagaatttagtctctgtgtcagcacagtgtaatctctattgctattgcccc 106 210445_ gctttcaccggcaagttcgagatggagagtgagaagaattatgatgagttcatgaagctccagggatctccagcgatgta at atcgaaaaggcccgcaacttcaagatcgtcacggaggtgcagcaggatgggcaggacttcacttggtcccagcactac tccgggggccacaccatgaccaacaagttcactgaggcaaggaaagcaacatacagacaatggggggcaagacgtt caaggccactgtgcagatggagggcgggaagctggtggtgaataccccaactatcaccagacctcagagatcgtggg tgacaagctggtggaggtctccaccatcggaggcgtgacctatgagcgcgtgagca 107 210511_ aaaggagcagtcgcacagacctttcctcatgctgcaggcccggcagtctgaagaccaccctcatcgccggcgtcggc s_at ggggcaggagtgtgatggcaaggtcaacatctgctgtaagaaacagactagtcagatcaaggacatcggctggaatg actggatcattgctccctctggctatcatgccaactactgcgagggtgagtgcccgagccatatagcaggcacgtccgg gtcctcactgtccaccactcaacagtcatcaaccactaccgcatgcggggccatagcccattgccaacctcaaatcgtg ctgtgtgcccaccaagctgagacccatgtccatgagtactatgatgatggtcaaaacatcatcaaaaaggacattcagaa catgatcgtggaggagtgtgggtgctcatagagttgcccagc 108 210519_ cagaccagtgatattccagaccccctgcagtggtaggagtccctgccattctgaaaggctggatgagcatcatagga s_at gagtagcttacacttacgctgccatgtatgacaaaggaccatccggagtggcattctgcatactgtggcaccaagtctt agaacctcaactgacatatagcattgggcacactccagcagacgcccgaattcaaatcctggaaggatggaagaaacg cctggagaatatagggatgagacaccactgtattagctccaagcagcctattgacctaaacttccaggcaggattcttaa tgaaaaaagaggtacaggatgaggagaaaaacaagaaataggcctactgtgggccatcacttgggcaagtccatccc aactgac 109 210559_ gtaacactctggtacagatctccagaagtattgctggggtcagctcgttactcaactccagttgacataggagtataggca s_at ccatatttgctgaactagcaactaagaaaccacttaccatggggattcagaaattgatcaactatcaggattacagagctt tgggcactcccaataatgaagtgtggccagaagtggaatattacaggactataagaatacatacccaaatggaaacca ggaagcctagcatcccatgtcaaaaacttggatgaaaatggcttggatttgctctcgaaaatgttaatctatgatccagcca aacgaatttctggcaaaatggcactgaatcatccatattttaat 110 210766_ ggttccatcaatggtgagcaccagcctgaatgcagaagcgctccagtatctccaagggtaccttcaggcagccagtgtg s_at acactgattaaactgcatttnctnaatgggctaaacccagatggtttcctaggaaatcacaggatctgagcacagctgc att 111 211429_ tactggaacctatgatctgaagagcgtcctgggtcaactgggcatcactaaggtatcagcaatggggctgacctctccg s_at gggtcacagaggaggcacccctgaagctctccaaggccgtgcataaggctgtgctgaccatcgacgagaaagggact gaagctgctggggccatgtttttagaggccatacccatgtctatcccccccgaggtcaagttcaacaaaccctttgtatctt aatgattgaacaaaataccaagtctcccctcttcatgggaaaagtggtgaatcccacccaaaaataactgcctctcgctcc tcaacccctcccctccatccctggccccctccctggatgacattaaaga 112 211506_ gtgtgaaggtgcagttttgccaaggagtgctaaagaacttagatgtcagtgcataaagacatactccaaacattccaccc s_at caaatttatcaaagaactgagagtgattgagagtggaccacactgcgccaacacagaaattattgtaaagctttctgatgg aagagagctctgtctggaccccaaggaaaactgggtgcagagggttgtggagaa 113 212063_ attgtaaatatttgtgtctcctgaagacttcccttaaaattagctctgagtgaaaaatcaaaagagacaaaagacatatcg at aatccatatttcaagcctggtagaattggatttctagcagaacattccaaaagttttatattgagattcataacaacaccaa gaattgattttgtagccaacattcattcaatactgttatatcagaggagtaggagagaggaaacatttgacttatctggaaaa gcaaaatgtacttaagaataagaataacatggtccattcacattatgttatagatatgtctttgtgtaaatcatttgattgagtt ttcaaagaatagcccattgttcattatgtgctgtacaatgaccactgttattgttactttgacttttcagagcacaccc 114 212070_ tccaaggactgagactgacctcctctggtgacactggcctagngcctgacactctcctaagaggttctctccaagccccc at aaatagctccaggcgccctcggccgcccatcatggttaattctgtccaacaaacacacacgggtagattgctggcctgtt gtaggtggtagggacacagatgaccgacctggtcactcctcctgccaacattcagtctggtatgtgaggcgtgcgtgaa gcaagaactcctggagctacagggacagggagccatcattcctgcctgggaatcctggaagacttcctgcaggagtca gcgttcaatcttgaccttgaagatgggaaggatgttctttttacgtaccaattct 115 212190_ cgatgcaagtgtttctgttctgggaggtattggagggaaaaaancaagcaggatggctggaacactgtactgaggaatg at aatagaaaggatccagatgtctaaaagattattaaactactgaactgttacctaggttaacaaccctgttgagtatttgctg tttgtccagttcaggaatttttgattgattgtctatatgtgcggatttcagaagaaatttaatcagtgtgacagaaaaaaaaat gttttatggtagatttacttntatgaaaaaaaaattatttgcatttaaattatttcccccatccccctccaaagtcttgatagc aagcgttattttgggggtagaaacggtgaaatctctagcctctttgtgatttgttgttgttgttgttgttgattatataatgcatgt attcactaaaataaaatttaaaaaactcctgtcttgctagacaaggttgctgttgtgcagtgtgcctgtcactactggtctgta ctccttggatttgc 116 212281_ tacagccaggcataacatatccactgtgtgcatagagggtctatcacgttgatgatggcattccatcagctttctctaagt s_at ctttgctcaagttcaaccttaaaatgatgttag 117 212344_ ggaaaacacctcatttgaccttgccagctgaccttcaaaccctgcatttgaaccgaccaacattaagtccagagagtaaa at cttgaatggaataacgacattccagaagttaatcatttgaattctgaacactggagaaaaaccgaaaaatggacggggca tgaagagactaatcatctggnaaaccgatttcagtggcgatggcatgacagagctagagctcgggcccagccccaggc tgcagcccattcgcaggcacccgaaagaacttccccagtatggtggtcctggaaaggacatttttgaagatcaactatatc ttcctgtgcattccgatggaatttcagttcatcagatgttcaccatggccaccgcagaacaccgaagtaattccagcatagc ggggaagatgttgaccaaggtggagaagaatcacgaaaaggagaagtcacagcacctagaaggcagcgcctcctctt cactctcctctgattagatgaaactgttaccttacccta 118 212353_ aatatccttgttgtgtattaggtttttaaataccagctaaaggattacctcactgagtcatcagtaccctcctattcagctcccc at aagatgatgtgatttgcttaccctaagagaggttncttcttattntagataattcaagtgcttagataaattatgttttctttaagt gtttatggtaaactcttttaaagaaaatttaatatgttatagctgaatctttttggtaactttaaatctttatcatagactctgtacat atgttcaaattagctgcttgcctgatgtgtgtatcatcggtgggatgacagaacaaacatatttatgatcatgaataatgtgct ttgtaaaaagatttcaagttattaggaagcatactctgattttaatca 119 212354_ gtgtgcacacggagactcatcgttataatttactatctgccaagagtagaaagaaaggctggggatatttgggttggcttg at gttttgattnttgcttgtttgtttgttttgtactaaaacagtattatcttttgaatatcgtagggacataagtatatacatgttatcca atcaagatggctagaatggtgcctttctgagtgtctaaaacttgacacccctggtaaatctttcaacacacttccactgcctg cgtaatgaagttttgattcatttttaaccactggaatttttcaatgccgtcattttcagttagatgattttgcactttgagattaaaa tgccatgtctatagattagtcaatatatattatacaggcttatcagtctcactgaggctgtcattgtgacaaagtcaaataaa cccccaaggacgacacacagtatggatcacatattgatgacattaagcattgccagaaaatgagcatgtgattacctcg actt 120 212531_ caagagctacaatgtcacctccgtcctgataggaaaaagaagtgtgactactggatcaggacattgaccaggagcca at gcccggcgagttcacgctgggcaacattaagagttaccctggattaacgagttacctcgtccgagtggtgagcaccaac tacaaccagcatgctatggtgacacaagaaagtactcaaaacagggagtacacaagatcaccctctacgggagaacc aaggagctgacacggaactaaaggagaacacatccgcactccaaatctctgggcctccctgaaaaccacatcgtcac cctgtcccaatcgaccagtgtatcgacggctgagtgcacaggtgccgccagntgccgcaccagcccgaacaccattga ggga 121 212942_ ccacagtccacggattgagagattcactcactaatgcaagggtctcacactgtgaaccacttaggatgtgatcactaca s_at ggtggccaggaatgagaatgtctaggctcagacataaaaaaagatatctatagaaagactcagagagtacatatgat cacagtacaggatctgtacataaaagtactacctaaaccattcaccaagagccaatatctaggcattacaggtagcaca aattacttattgcttagaaaattgtcctccagttatactgatgtaagacttaagtgagaaggtcataaggaaagcaacgct cctctgaaatgcagtcattactgagccgaaatagctggtccatacgggagttagatgtatagagtgatgtatgtaaacat ttcttgtaggcatcaccatg 122 213880_ caatatctgacaccactaggactcaagagactcagtaacgtattatcctgatatttagcaggattagctgtgactctctgg at ataacccacttgatgaaggaacattacactctgcttattccatattaatactgtgaaggtatataagaagcaagaattaaat aagaaaagtcaaagtattaaacttaccactattatcctatattagcacaatacatccaaaccaaatggctgaaggtagata attatatataagcatgatattagatcagatgattaacaggatagaaaaaatacataatgagatgattataagatgtgtaaa tatagaactgtataattactatagtaaaggacagtaacattaaggaccatgataatgataataaaccagtacagtggcata ttctttgatttatattgtgtttctctgcccatt 123 213905_ cacaaaaccccagggacagcggtctccccagcctgccctgctcangccttgcccccaaacctgtactgtcccggagga x_at ggagggaggtggaggcccagcatcccgcgcagatgacaccggattcctagaagcccctcacccccactggcccact ggtggctaggtctccccaatccactggtccagcgcaaggaggggctgcactgaggtcggtggctgtctaccattaaa gaaacaccgtg 124 213975_ gaaataacccagacttaatcagaatgatncgattatgcccaatattaagtananaatataagaaaaggaatcaaaataga s_at tcaaggcaaaataccagctgatgaaggcatctgatgccacatctgacagtcatctccaaaaacagtaaaaataaccact attgagggcaatatgaaattataaaggagtagaataccaaatgatagaaacagactgcctgaattgagaattagatana aaagtgtgatctactaaattgctgaccaaatagattaaataattcatgtattatgattaaatctgaggcagatgagcttaca agtattgaaataattactaattaatcacaaatgtgaagaatgcatgatgtaaaaaatacaaacaactaattaaaggca 125 214022_ tcaacaccctcacttgaactggtgctgtctgggcacatagcattcgcctactccgtgaagtctagggacaggaagatggt s_at tggcgacgtgaccggggcccaggcctatgcctccaccgccaagtgcctgaacatctgggccctgattctgggcatcct catgaccattggattcatcctgaactggtattcggctctgtgacagtctaccatattatgaacagataatacaggaaaaac ggggaactagtagccgcccatagcctgcaaccatgcactccactgtgcaatgctggccctgcacngctngggctgag cccctgcccccaggtcctgcccctagatacagcagatatacccacacacctgtctacagtgtcattcaata 126 214235_ ggtgaggggatgacccctggagatgaagggaagaggtgaagccaagcaaaaatgcctcctcaccactccccaggag at aattatataaaaagcataatcactgattccacactgacataatgtaggaagcctctgaggagaaaaacaaagggagaaa catagagaacggagctactggcagaagcataagatctagtacaatattgctggccctggacacctgatactgaatcac aata 127 214651_ gtgattcaaacactgtgtactgggtgatgcacccattgtgattgtggaagatagaattcaatagaactcaggagatatga s_at ggggaaaaaaacagttgcatagagtatagctctgtagtggaatatgtcttctgtataactaggctgttaacctatgattgtaa agtagctgtaagaatacccagtgaaataaaaaaaaatataagtgactcggggatgcatagattcatcattactccacca aaaaatgcgggcatttaagtctgtccattatctatatagtcctgtcagtctattgtatatataatctatatgattaaagaaaatat gcataatcagacaagcgtaatgcataatcagacaagcagaatattgatagcaccagacgaacagtgaggaaattcgga gctatacatatgtgcag 128 214974_ agtcagtgagtcaaatatccagataatgctgtaaagatattatacaaatatactgataagctatacacctagtaggaaat x_at ccacccattaaagagaaaatgtgacacagtgaaaaggcagtaggaaagctcctcccataancataaaccataaatg acaaacctaggtaattaatggttgtgaatttctatttttgattgatttaatgaacatttgtattcagaataggattctgtgataat atttaaatggcaaaaacaaaacataattttgtgcaattaacaaagctactgcaagaaaaataaaacatttatggtaaaaac gtatgtatttatatattatatatttatatataatatatattatatatttagcattgctgagctttttagatgcctattgtgtatattta aaggttttgaccattttgttatgagtaattacatatatattacattcactatattaaaattgtacttttttactatgtgttctcattgg ttcatagtctttattttgtcctttgaa 129 215091_ tatgtcgctgtccaagagaaggctgtggaagaacctatacaactgtgtttaatctccaaagccatatcctctcatccatga s_at ggaaagccgccatttgtgtgtgaacatgctggctgtggcaaaacatttgcaatgaaacaaagtctcactaggcatgctgt tgtacatgatcctgacaagaagaaaatgaagctcaaagtcaaaaaatctcgtgaaaaacggagtttttggcctctcatctca gtggatatatccctcccaaaaggaaacaagggcaaggcttatcttttgtgtcaaaacggagagtcacccaactgtgtgga agacaagatgctctcttacagttgcagtacttacccttggctaagaact 130 217430_ agggcctaagggtgacagaggtgatgctggtcccaaaggtgctgatggctctcctggcaaagatggcgtccgtggtct x_at gaccggccccattggtcctcctggccctgctggtgcccctggtgacaagggggaccccattcccgaggagctttatgag 131 217523_ gagttattattatctcatagcgtatgattcttgnacagccttgaataattttgattgacctctgggatgttattaaagcctaacgt at tccttctattctcacaaattttcgttatgacttcagaaggatcattaactctggtatctgtttgtttgcttgtatggcaccaataag cagatttcttctttctaatctatggattagtatagaccaggagaaggctaatacagagactatgaaacgggaataagttttttt aacgatatggcaaaattgtgactctgaaagatcattcatgtatattctaaaattaccacagtcataaaaagtcttggactttca tgaggaaatagcatagctagatatgaaaaaatatagaaaatcttcatcaatggaactattcttggggtagacactaatcata tgaaaagacaaatgctcattccctaagatagcctga 132 217867_ gcttctacgtcatcttcgacagagcccagaagagggtgggcttcgcagcgagcccctgtgcagaaattgcaggtgctgc x_at agtgtctgaaatttccgggcctttctcaacagaggatgtagccagcaactgtgtccccgctcagtctttgagcgagcccat tttgtggattgtgtcctatgcgctcatgagcgtctgtggagccatcctccttgtcttaatcgtcctgctgctgctgccgttccg gtgtcagcgtcgcccccgtgaccctgaggtcgtcaatgatgagtcctctctggtcagacatcgctggaaatgaatagcca ggcctgacctcaagcaaccatgaactcagctattaagaaaatcacatttccagggcagcagccgggatcgatggtggc gctttctcctgtgcccacccgtcttcaatctctgttctgctcccagatgccttctagattcactgtctt 133 217996_ gaagtgggacgagcacatttctattgtcttcacttggatcaaaagcaaaacagtctctccgccccgcaccagatcaagta at gtttggacatcaccctactgaaaacttgcgattcttcttagttttctgcatacttttcatcacgatgcaggaaacgatttcgagt caagaagacttttatttatgaacctttgaaaggatcgtcttgtatggtgaattttctaggagcgatgatgtactgtaattttatttt aatgtattttgatttatgattatttattagttnttttaaatgcttgttctaagacatttctgaatgtagaccattttccaaaaaggaaa ctttattttcaaaaacctaatccgtagtaattcctaatcttggagaataaaaaagggcggtggaggggaaaacattaagaat ttattcattatttctcgagtactttcagaaagtctgacactttcattgttgtgccagctggtt 134 218086_ ggcacagagcgcggagatgtaccactaccagcaccaacggcaacagatgctgtgcctggagcggcataaagagcca at cccaaggagctggacacggcctcctcggatgaggagaatgaggacggagacttcacggtgtacgagtgcccgggcc tggccccgaccggggaaatggaggtgcgcaaccctctgttcgaccacgccgcactgtccgcgcccctgccggccccc agctcaccgcctgcactgccatgacctggaggcagacagacgcccacctgctccccgacctcgaggcccccgggga ggggcagggcctggagcttcccactaaaaacatgattgatgctgtgtgcttttggctgggcctcgggctccaggccctg ggaccccttgccagggagacccccgaacctttgtgccaggacacctcctggtcccctgcacctctcctgttcggtttaga cccccaaactggagggggcatggagaaccgtagagcgcaggaacgggtgggtaatt 135 218211_ gccacaccttcgcgaaacctgtggtggcccaccagtcctaacgggacaggacagagagacagagcagccctgcact s_at gttttccctccaccacagccatcctgtccctcattggctctgtgctttccactatacacagtcaccgtcccaatgagaaacaa gaaggagcaccctccacatggactcccacctgcaagtggacagcgacattcagtcctgcactgctcacctgggtttact gatgactcctggctgccccaccatcctctctgatctgtgagaaacagctaagctgctgtgacttccctttaggacaatgttg tgtaaatctttgaaggacacaccgaagacctttatactgtgatcttttacccctttcactcttggctttcttatgttgc 136 218507_ tggtgtatgctgtgctttcctcagcagtatggctctgacatctcttagatgtcccaacttcagctgttgggagatggtgatattt at tcaaccctacttcctaaacatctgtctggggttcctttagtcttgaatgtcttatgctcaattatttggtgttgagcctctcttcca caagagctcctccatgtttggatagcagttgaagaggttgtgtgggtgggctgttgggagtgaggatggagtgttcagtg cccatttctcattttacattttaaagtcgttcctccaacatagtgtgtattggtctgaagggggtggtgggatgccaaagcctg ctcaagttatggacattgtggccaccatgtggct 137 218704_ gaatactgctggactttatctgggcagaggaaggatggaatgaaggtagaaaaggcagaattacagctgagcgggga at caacaaagagttcactctgggaaaagattgtcttagagcaaggatggaaaatggggacaacaaaggaaaagcaaagt gtgacccagggtaggacagcccagaggcccagctccccagtataagccatacaggccagggacccacaggagagt ggattagagcacaagtctggcctcactgagtggacaagagctgatgggcctcatcagggtgacattcaccccagggca atgcctgaccactcaggcccctcaggcattatcccataggaatgtgaatgtggtggcaaagtgggcagaggaccccacct gggaaccataccctcagttagtggggagactagcacctaggtacccacatgggtatttatatctgaaccagacagacgc ttgaatcaggcactat 138 218796_ gagacagacttggcaagggaccccctggactgagccagtagctgccatctggaaattcctcattagcctctccttagag at gtgaatgtgaatgaagcctcccaggcacccgctgaatactgaggccagcttaaagctcagaagtggataggcatagg aaaatctggacacatcataaagaacttgatttgaaatgattctatagaaacaagtgctaagtgtaccgtattatacttgatga ggtcatactcagtcctatactcagactattatatagaacctagtcagactttaagattataactggtcctacattaaaataat gatctcgatgtcagatatacctgatgctgctgagaacatctctgcctaatttaccaaagccagaccacagttcaacatgc accttagatttcatagagtctgacataccatgaaaacaaaggaaccaactagattaaccaaactagtaggttacagatt caggggagcgtttcttccatgaca 139 218872_ catgtacgactcggacagcgacggccgcatcactctggaagaatatcgaaatgtaaagtggtcgaggagctgctgtcg at ggaaaccctcacatctagaaggagtccgctcgctccatcgccgacggggccatgatggaggcggccagcgtgtgcat ggggcagatggagcctgatcaggtgtacgaggggatcaccacgaggacttcctgaagatctggcaggggatcgacat tgagaccaagatgcacgtccgcaccttaacatggaaaccatggccctctgccactgacccaccgccacctccgcgga gagactgcactttgcaatggggccgcctccccgcgtagctggagcagcccaggcccggcggacagcctcttcctgca gcgccggtacatagccaaggctcgtctgcgcaccagtgtcagtagggtatggtatgtgggacttcgct 140 218963_ gaggaggaactgacgcagctacgccacgaactggagcggcagaacaatgaataccaagtgctgctgggcatcaaaa s_at cccacctggagaaggaaatcaccacgtaccgacggctcctggagggagagagtgaagggacacgggaagaatcaa agtcgagcatgaaagtgtctgcaactccaaagatcaaggccataacccaggagaccatcaacggaagattagactagt caagtgaatgaaatccaaaagcacgcatgagaccaatgaaagtaccgcctgagtaaagtctattacccccaaggaaa gtccagcacagacaccagtgagtgagactaaaagatacccaggaattatcagactcagaaactatattattatttctgta acagtctcaccagacactcataatgctcttaatatattgcactatctaatcaaagtgcgagatatgagggtaaagctctact ttcctactg 141 218984_ aatcctgcaattctcaatcttgcactgcagcctcgacctcccaggctccagtgactctcccacctcagcctcctaagtagct at gggagtacaggcgcgcaccaccacgcctagctgatttagtattatttgtagagacgggggatggccatgagccgagg ctaactcctgggattacaggcatgagctgtgctggccgggattatacttgatgtaaacgtgtacagctgattattagttaa ggtctaattatactctaggtgccattatgacagaactattccactggactggtatttgctcaaaaataaataatggtagaga agaaaactataaaaatggacaaggattcactatcagtagcgataccctagtcaccagtggctaggtataccatgtctg gcattgcataaacactctggtgtgaaaggataaatatgcctactaaagagtatatcaaaattgtatcaattatattactatga tactagaaacaaatgtaataaatattataaaatctcctactactggttatgta 142 219630_ ctcgagcaatcgcattgcagtcaaccacttctggtgccaggaggagccggagcctgcacacatgatcctgaccgtcg at gaaacaaggcagatggagtcctggtgggaacagatggaaggtactatcgatggcggccagatcaggtccagtgagc atgagaatgcctatgagaatgtgcccgaggaggaaggcaaggtccgcagcaccccgatgtaaccactctgtggctcc aaccccaagactcccaggcacatgggatggatgtccagtgctaccacccaagccccctccactagtgtggaatctgca atagtgggctgactccctccagccccatgccggccctacccgcccttgaagtatagccagccaaggaggagctcaga ccgtgtctaggttggggctcg 143 219682_ gagagaaaacaatatagccccctaccatacccaatcattgccctcaaatcagtgacccaagggagggggggatttaa s_at agggaaggagtgggcaaaacacataaaatgaatttattatatctaagctctgtagcaggattcatgtcgactagacagttc tactctacctgtatatgcaataacaaggattaaaaaaaaaaaaaaaaagtgagactattagacaaagtatttatgtaattatt tgataactcagtaaataggtggaatatgaatgatggaaaattaaactttaatttattgacattgtacatagctctgtgtaaata gaattgcaactgtcaggattgtgacttgattcattagagggatataccaggtcacagaattgctgttaacactagaaaac acacttcctgcaccaacaccaataccattcaaaagagagtctgcaacatattgattattataatgtccaaaagtggggg aaagtgctatacctattacaccaaaattggggaaggagtgccactaccagc 144 219727_ ttagcactgaaagtctcttgccccaggaaaccccatcagtcccaggcagattgggacagctggtcaccttacgcaagag at ccaggctgaaacatcccctccatactcagctattaactatcattcattacatcgggctattcctaaaaagctgagctgta aaatatatacatcgaggtataataaataatcatgtacatgattaccaccacccaggtcaagacatagaatgatcaacatttc catcaccccagaaactccccagtaccccatccacttcgtctcccctagctcctagaagcaaccactgatgtgatactac caaatccagattggtcctactaaatatactcattgagactggcctatttactcaccataatgcctagtaattc 145 219787_ tagctgatcagagagagtacggtatatttatggtaatatatccactagcaaatcttgatttagatgatagtgtgtggaatata s_at attgaaggataagaccatgggaaaattgtggtaaagactgatgtaccatcatgaaataattctgaagagccatcagatt actaatcactgtgaaatgcatagatatgcgcatgacaactattattgtggtcttataattaaatgtaaaattgaaaattcatttg ctgatcaaagtgtgatatattcacaatagccatttatagtcagtaattcagaataatcaagttcatatggataaatgcattat atttcctatttctttagggagtgctacaaatgtttgtcacttaaatttcaagtttctgttttaatagttaactgactatagattgttttc tatgccatgtatgtgccacactgagagtagtaaatgactattgctacatata 146 219911_ gtgtaccagaattcggccatgagccgctacatactcatcatggggctcctgtacaaggtgctgggcgtcctcactagcc s_at atagcctgatcttatacaagcccctgtcggagtcttcagatggcctggaaacttgtctgcccagccagtcctcagcccct gacagtgccacagatagccagctccagagcagcgtctgaccaccgcccgcgcccacccggccacggcgggcactc agcatttcctgatgacagaacagtgccgttgggtgatgcaatcacacgggaacttctatttgacctgcaaccttctacttaa cctgtggataaagtcggctgtgacctcctgtccccagagctgtacggccctgcagtgggtgggaggaacttgcataaat atatatttatggacacacagtagcatcagaacgtgatatagaatgtgattatacccgatcgtgtgtggtgtgcgtgaggac aaactccgcaggggctgtgaatcccactgggagggcggtgggcctgagcccgaggaaggcttgtgtgtcctcagtta a 147 219955_ gaagagcaacattcgatgataggaattccagaaaaggagagttatgagaatagggcagaggacataattaaagaaata at attgatgaaaactagcagaactaaagaaaggacaagtcttgagattgtcagtgcttgtcgagtacctagtaaaattgatga aaagagactgactcctagacacatcaggtgaaattaggaattctagtgataaagagaaaataataagggcactagaga gagaagagaaattacctaccaaggaacaagaatcaggagacagcagacttatcactggacacactggatgctagaagt aaatggagcaatgtatcaaagactgctggaaaaaggattaatcctagaatcctatatccagccaaaatggcatttgatat aggggcaaaacaaaggtatacttagtattgaagaatttagagattatgattgcatatgcccaccttgagagaattactggg gaataatataccttagcacgccagggtgactaca 148 219956_ ttgcttgttccccggaggttgaagctacagtgagccttgattgtgtcactgcactccagcctgggcaacaggtaagactct at gtctcaaaaaaaaaacaaaaaagaagaagaaaagtacactacagccatgtcctattccttgatcatccaaagcacctgc agagtccagtgaaatgatatattctggctgggc 149 221577_ gacggcgtcaaggtcgtgggacgtgacacgaccgctgcggcgtcagctcagccttgcaagaccccaggcgcccgcg x_at ctgcacctgcgactgtcgccgccgccgtcgcagtcggaccaactgctggcagaatatcgtccgcacggccccagctg gagagcacttgcggccgcaagccgccagggggcgccgcagagcgcgtgcgcgcaacggggaccactgtccgctc gggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctgtc gccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagaccgggcggcaaacatgcacgcgcag atcaagacgagcctgcaccgcctgaagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaatcccat ggtgctcattcaaaagaccgacaccggggtgtcgctccagacctatgatgacttgttagccaaagactgccactgca 150 221729_ tggaattagaccataggcattgaactacataggaaaaatgacccaacatacttagcatgagctacctcatctctagaag at ctgggatggacttactattcttgatatatatagatactgaaaggtgctatgatctgttattattccaagactggagataggca gggctaaaaaggtattattattatcattaatgatggtgctaaaattatcctataaaattccttaaaaataaagatggataatc actaccattgtgaaaacataactgttagacttcccgtttctgaaagaaagagcatcgttccaatgcttgttcactgttcctctg tcatactgtatctggaatgctttgtaatacttgcatgcttcttagaccagaacatgtaggtccccttgtgtctcaatacttttttttt cttaattgcatttgttggctctattttaattt 151 221730_ tagattccggtatatcgacttcaagacacttgctctaagcggaatggaaatgtgggcaagactgtattgaatatagaaca at cagaatgtggcacgcttgcccatcatagatcttgctcctgtggatgaggcggcacagaccaggaattcggcgttgaaatt gggccagatgattgtgtaaagtaagccaagacacatcgacaatgagcaccaccatcaatgaccaccgccattcacaag aactagactgatgaagttgatcctgagactcttgaagtaatggctgatcctgcatcagcattgtatatatggtcttaagtgcc tggcctccttatcatcagaatatttatatacttacaatcctcaagattaattgatataaatattatcaatacaacagataggtt taagatgaccaatgacaatgaccacctt 152 221731_ tacagcaccgatggccatgtaaataagatgatttaatgagatataatcctgtatataaantaaaaagtncncaatgagat x_at ttgggcatatttaatgatgattatggagccttagaggtattaatcattggacnggctgatttatgtagataggctggaaatg gtttcacttgctctttgactgtcagcaagactgaagatggcttttcctggacagctagaaaacacaaaatcttgtaggtcatt gcacctatctcagccataggtgcagatgatctacatgatgctaaaggctgcgaatgggatcctgatggaactaaggact ccaatgtcgaactcttctttgctgcattcctttttcttcacttacaagaaaggcctgaatggaggacttttctgtaaccaggaa cattattaggggtcaaagtgctaataattaactcaaccaggtctactattaatggattcataacactaactcataaggttac cgatcaatgcatttcatacggatatagacctagggctctggagggtgggg 153 221922_ gtaaatagttaaccacagtagtctattaaggcattaatacactctggacatgcgcgatgagggtggaggggtcctgtaag at gtgcttcatcgtctgtgattactgcttgggatgtgttctttggcagcttgtgagattactttacctagtgtttataaagtaggaag ttaagtgaatcatagattagaatttaatactcttatggaaataattattaacatcttaattgacaatggcgattatataca 154 221923_ tagtccatactgagtgtcatcaacaatccagactgaagtcactatataatctcaatcccatactgatttgccacccatgcct s_at cttcaggctggaaacaatctcttggttccctaaagcactttcttctgactgctgtgattcagtgaaccttgccctttgctttctat tacttgtgcatttgcctcacctgacaatgattaaatcgcctagtatctccttagctgctcaataa 155 222449_ aatatgtcagtgcttgcttgatggaaacttctcagtgtctgagagactttaagggagaaatgtcggaatttcagagtcgcct at gacggcagagggtgagcccccgtggagtctgcagagaggccttggccaggagcggcgggctttcccgaggggcca ctgtccctgcagagtggatgatctgcctagtgacaggttatcaccacgttatatattccctaccgaaggagacaccattcc cccctgacccagaacagcattaaatcacaagcaaaataggaaagttaaccacggaggcaccgagaccag 156 222450_ ggctgggggagagccgggacattccctgtcctcattggtcgtccctatgaattgtacgatcagagaaattattacctatgt at gcaacacgaagatccagaaccataaaatatcccgtcgataaggaaagaaaatgtcgttgagttgatactggaaactgc ttgaaatcttgctgtactatagagctcagaaggacacagcccgtcctcccctgcctgcctgattccatggctgagtgctga accaatgattcacgaggacctggcgtgggaactgctctcattgcagccccatacccaagctctgacaagttaaactta tgtaagctaccgtggcatgcggggcgcgcacccacgtccccgctgcgtaagactctgtataggatgccaatccacagg cctgaagaaactgcttgagtg 157 222549_ gtgagtatggcccaatgctttctgtggctaaacagatgtaatgggaagaaataaaagcctacgtgttggtaaatccaacag at caagggagatattgaatcataataactcataaggtgctatctgacagtgatgccctcagagctatgctgttagctggcag ctgacgctgctaggatagttagtaggaaatggtacttcataataaactacacaaggaaagtcagccaccgtgtcttatgag gaattggacctaataaatatagtgtgccaccaaacctgagaatatatgcttaggaagttaaaatttaaatggcattgccac atacatagatatcatgatgtgtgagtgtaattccatgtggatatcagttaccaaacattacaaaaaaatatatggcccaaaa tgaccaacgaaattgttacaatagaatttatccaattagatctattatattatctaccacacctggaaacagacc 158 222608_ catggatacatttactcagctactatatatgcagtgtggtgcacattacacagaattctggcttcattaagatcattatattgn s_at ctgcgtagcttacagacttagcatattagattactactcctacaagtgtaaattgaaaaatattatattaaaaaagtaaactg ttatgaagctgctatgtactaataatactagcttgccaaagtgtagggattgagttgatgatgatgatgataggacatga acaacagtgtctagaaacccattagaaagtggaaaattattaagtcacctatcaccataaacgcattattaaaattataaa atattgtaaagcagggtctcaactataaatacactagaacttatctctgaattattaaagttattatgacctcatttataaaca ctaaattctgtcacctcctg 159 222696_ gccgctgtgattcgtggaaatgacagaccttgattattgatctgatttgattacattagtcattggaccacagccattcag at gaactaccccctgccccacaaagaaatgaacagagtagggagacccagcagcaccatcctccacacaccacattag attgttcgggatagtgttaagttaatctgtacattctgatgccattgttacttgtactatacatctgtatatagtgtacggcaaa agagtattaatccactatctctagtgcttgactttaaatcagtacagtacctgtacctgcacggtcacccgctccgtgtgtcg ccctatattgagggctcaagctaccatgattagaaaggggatatgtataaatatatatatgccatttattacaagtcagt 160 223062_ ggagtggataagagtgccaggcgaagggcaaactgtagatcgatattatgctgttattacaggagaagtgacatacat s_at atatatgatatattagcaaggtctgatttaataccatatacatatatactatacatttatatactaataatacagttatcactgat atatgtagacactatagaatttattaaatccttgaccagtgcattatagcattccattagcaagagagtaccccctccccag tatcgccacctctattaagctgattatgaaaaagacctagaagacttgattcattataccattattccataggtagaagag aaagttgattggaggagatttcaattatgccattaaactaaacatttctgttaaattaccctatcattgactctactgattatt gtaatgtatgactacgagagtgatactagctgaaaagtctacccctattgatatctattgtca 161 223447_ ttcctgtgcaagtaccgaccatagagcaagaatcaagattctgctaactcctgcacagccccgtcctcttcctttctgctag at cctggctaaatctgctcattatttcagaggggaaacctagcaaactaagagtgataagggccctactacactggcttntta ggcttagagacagaaactttagcattggcccagtagtggatctagctctaaatgtttgccccgccatccattccacagtat catatccctcctcccctgtctctggctgtctcgagcagtctagaagagtgcatctccagcctatgaaacagctgggtatt ggccataagaagtaaagatttgaagacagaaggaagaaactcaggagtaagatctagacccdtcagatctacaccct tctgccctctctccattgcctgcaccccaccccagccactcaactcctgcttgtttttcctttggccatagg 162 223970_ ggagctcagagatctaagctgctttccatatttctcccagccccaggacactgactctgtacaggatggggccgtcctctt at gcctcatctcatcctaatccccatctccagctgatcaacccggggagtactcagtgttccttagactccgttatggataag aagatcaaggatgttctcaacagtctagagtacagtccctctcctataagcaagaagctctcgtgtgctagtgtcaaaagc caaggcagaccgtcctcctgccctgctgggatggctgtcactggctgtgcttgtggctatggctgtggttcgtgggatgtt cagctggaaaccacctgccactgccagtgcagtgtggtggactggaccactgcccgctgctgccacctgacctgacag ggaggaggctgagaactcagttngtgaccatgacagtaatgaaaccagggtcccaaccaagaaatctaactcaaacgt cccact 163 224428_ gcaaagtttatttcagttcacatgtaaggtattgcaaataaattatggacaattngtatggaaacttgatattaaaaactagtc s_at tgtggttctttgcagtttcttgtaaatttataaaccaggcacaaggttcaagtttagattttaagcacttttataacaatgataagt gcctttttggagatgtaacttttagcagtttgttaacctgacatctctgccagtctagtttctgggcaggtttcctgtgtcagtat tccccctcctattgcattaatcaaggtatttggtagaggtggaatctaagtgtttgtatgtccaatttacttgcatatgtaaacc attgctgtgccattcaa 164 224646_ agacggccttgagtctcagtacgagtgtgcgtgagtgtgagccaccttggcaagtgcctg x_at 165 224915_ ggagtgtggtacttctcctagttgcagtcaggcttcatacgctnttgtcctgcccgttagagcagccagcgggtacagaat x_at ggattttggaagagggagtcaccactggacctccaaggaagccacgtgcagacatctacaaccttcgatctcctgacga gtttattgaggccaaaaccaggattgattgaaccaggatgaatgcgggtgaggaagtagaatatatatatacatataaaa ttggttgggagccacgtgtaccagtgtgtgttgatcttggcttgattcagtctgccttgtaacagaaactggcgatggaatat gagaggagccctctggaaagaaaaggacagaccctgtgctttcatgaaagtgaagatctggctgaaccagttccacaa ggttactgtatacatagcctgagtttaaaaggctgtgcccacttcaagaatgtcattgttagactttgaaatttctaactgccta cctgca 166 225295_ agggctgtaacagttgctgctagtattagggttccacatcattctaatgtatagtttcaagtcttaatagacaatctgaattcca at ctacatttcttttggctccaacattcatttagcttgaccagtctaatttaaaatgtgtttgttggaggtcattaacgttacttgtac aatgctgtcactgtgtgacatccatatgaattttggtatatatcaatcaatcaatcaatcannnncattgcattcaatcaatca gctgtgattgattnnnnatgcttagaaatactatagtaactagatgcagtgtgaattattccattaacaaacaaacaagtca gtggcttaaatgtgattatggtcctgcaaggtgattcttgctaaaatatctaaacttttgattgattaactgaatcattnttaact taaaaagctggaaaatatcaaatgctgattnttttnncattgtcaacagtggtgtgtcattttatgtatgttcctaatgcttatg gaactcctcca 167 225520_ ggaacgatgagcaccatgccaggactgcccacccggccctgatttatgacatagatcttgataccgaaacagaacaag at ttaaaggcttgttctaagtggacaaggctctcacaggacccgatgcagactcctgaaacagactactattgcattttgct gcagttggagaagaaactgaatttgaaaaatgtctgttatgcaatgctggagacatggtgaaataggccaaagatttcttct tcgttcaagatgaattctgttcacagtggagtatggtgttcggcaaaaggacctccaccaagactgaaagaaactaatttat ttctgtttctgtggagtttccattatttctactgcttacactttagaatgtttattttatggggactaagggattangagtgtgaac taaaaggtaacattttccactctcaagttnctactttgtattgaactgaa 168 225541_ gaaacacaaccaagacgcgaggatcnnnnnctntnnnnnnnnnnnnnctngcaagatggcgccgcagaaagac at aggaagcccaagaggtcaacctggaggtttaatttggaccttactcatccagtagaagatggaatttttgattctggaaattt tgagcaatttctacgggagaaggttaaagtcaatggcaaaactggaaatctcgggaatgttgttcacattgaacgcttcaa gaataaaatcacagttgtttctgagaaacagttctctaaaaggtatttgaaataccttaccaagaaataccttaagaagaac aatcttcgtgattggcttcgagtggttgcatctgacaaggagacctacgaacttcgttacttccagattagtcaagatgaag atgaatcagagtcggaggactaggcaaaggctccccttacagggctttgcttatt 169 225664_ ggaacccagagctgctgtgtatacgagcgggcagatatcattgctatacttattacaattcaattacaccacgattcaaat at aaacccctcctaaaaccaaaaaggagggaaacgtcaactccattgcaattacttatcacctcactatctctgaatacgcc ggggcatagaatgctcgtatacatctcataacaaccacaaaccaaagccatgtagatgaagttagtgcatcaacgggat acagaccatattgccaaaacctccagattagacacactaacataataccaaattgcagattaactgcagagagggaatt gcatgtttgtgttgta 170 225681_ aattaatattcatcgcacacactgtggaaggactagtgaaggaaaggtgctggattagtggatgagctatctgggagg at cacttgacagattacccaaaaggagatgcactactggatggaattcagtactcgcatcattattgaagaactaccaaaat aaatgattaattacatagctacctcattatattatgccaggaatggacacttaaatgacatataaataagatatgtatacat ctgaatgaaaagcaaagctaaatatgatacagaccaaagtgtgatacacactgataaaatctagcattattcattagcac aatcaaaagtggatcaatattatatagaggaagaatactacacatagtcacattctctcaacctataataggaatattga gtggtcattgattactatagtatagcattataaaaaaatataaaagctaccaatctagtacaatag 171 225767_ ccgtgtgagcgatcgcggtgggttcgggccggtgtgacgcgtgcgccggccggccgccgaggggctgccgttctgc at ctccgaccggtcgtgtgtgggagacacggaggcgctctgcctcggaaggaaggaggtgggtggacgggggggcct ggtggggttgcgcgcacgcgcgcaccggccgggcccccngccctgaacgcgaacgctcgaggtggccgcgcgca ggtgtttcctcgtaccgcagggccccctcccttccccaggcgtccctcggcgcctctgcgggcccgaggaggagcgg ctggcgggtggggggagtgtgacccaccctcggtgagaaaagccactctagcgatctgagaggcgtgccagggggt ac 172 225799_ aaatgactggatggtcgctgctattaagatcaaattgacattccagacaagcggtgcctgagcccgtgcctgtcacagat at cacacagcacagacctgggaaggtggagccaccagcctctccntgaataactgggagatgaaacaggaagctctatg acacacttgatcgaatatgacagacacngaaaatcacgactcanccccctccagcacctctacctgagcccgccgatc acagccggaatgcagctgaaagattccctggggcctggaccaaccgcccactgtggactctgaggcctctgcatttgc gggtggtctgcctgtgatattttggtcatgggctggtctg 173 225806_ tcttctcaggtcacttgtacacttggtttcctagtagaagctcacttgccacctctcaggggggtcccggattgcatccatca at caatcccaaaactngagaggggggaactggagggagcaaaacactgatagatactagtcagtagcagaaactaga cacctaaagctagatctataaaaccaaatactgaaaacagtagcttaaagaaatgacttaatgactaatagccaaaagc tcaaacctattaggtgtgatatatccatttaggtgtcctattcattagtcatgctaggatatacaaggatttatatctattcatc caagagtacactgagntattatcagcaacataaaatatcaaatagcagcactagtaaatgatgagattgcacctaccat atggatgtcttt 174 225835_ aatgcattactacacttaacactagacaccaggtcgaaaattacaaggaatagtacttatacaacaattcaagagatgct at agctagtgagaagctaaaaatagattatttatgctgaattgtgatatatatgccaaantatatagactaatcattgatgata gcttggaaataaataattatgccatggcatagacagacattaacctataagaattaaattgagatagagagaatggtggt gagagctgattattaacagaactgaaatcaaataatatagaacattattccatagtatataggatccattacattcataat atgcaactgacattacatattattaagactatggaaataaataaagataaagctctggtggatgattatctgctaagtaagt ctgaaaatgtaatattagataatactgtaatatacctgtcacacaaatgatactaatgattaaccagagtattgcagagct gctttgtacagaggtt 175 226227_ gtacactcctagagcagtcaggcacatacgctattgtcctgcccgttagagcagccagcgggtacagaatggattagg x_at aagagggagtcaccactggacctccaaggaagccacgtgcagacatctacaaccacgatctcctgacgagatattga ggccaaaaccaggcatgattgaaccaggatgaatgcgggtgaggaagtagaatatatatatacatataaaaaggagg gagccacgtgtaccagtgtgtgagatcaggcagattcagtctgccagtaacagaaactggcgatggaatatgagagg agccctctggaaagaaaaggacagaccctgtgattcatgaaagtgaagatctggctgaaccagaccacaaggaactg tatacatagcctgagataaaaggctgtgcccacacaagaatgtcattgaagactagaaatactaactgcctacctgca 176 226237_ gaagaggagcaacatctatgccaaatactgtgcaactacaatggtgctaatctcagacctaaatgatactccatttaaata at aaaaagagattaaataattatctatgtgcctgtatacccattgagtgctgcacaacatgaaacatattagtgtaaaagcag atgaaacaaccacgtgactaaagtctagggattgtgctataatccctatttagacaaaattaaccagaattcaccatgtga aatggaccaaactcatattattgaatgtaaatacagagattaatgcagtatgacatcccacaggggaaaagaatgtctgta gtgggtgactgaatcaaatatatatagaatacaatgaacggtgaacagactggtaacttgatgagacccatgacagata gagacttg 177 226311_ aaacgacgcaaatctctgagctggggaccacttggagaaccggcttagtaacagtcctgatcttcgcaagccagcttctt at ctgcatctgaggggctcctggcgcccagaggaggcagacagatgtcttctagctgagtttctaaccgcatgatgagact cagaccttccgctgcactagaaaatctgcaacagtgtccctgagtcacttctccttagtgggcagactcgtgttagatttgt ggaacccagctctctgatttactccttttggaaaacccatggaatttcatgtataaggctttcatttgtattttaaggtttttctgtt tgttttgagtatatacatggtgctcaatagcaacatcttagcagatgaagcagtttatgattccactccctcctgtatgacagg tagccactatactgaatcaaggtgctgaactcaaatcacaaaattctggcttaccgatacaacaaccaatac 178 226360_ gtcccactgctcacatacttatgtgctgctagtctctactcgaagttcgtgcaggactaatgcttttaaaatgaggtctaaaa at aataattactagtcgagactattattctttaaacagaactgcctttttctactctttatgtaaactctttctattgtgttggtctaacn aggcactattttaaaattattaatttttcccatagcacttaaaagagattttgtaaagaccttgctgtaaagattttgtaataaaa tggtctaagggctctttttccaacattaccatttttaaaaaatgttttaaaagctagaagacaacttatgtatattctntatatgta tagcagcacatttcatttatggaaatatgttctcagaatatttatttactaatatatttatcttaagccatgtcttatgttgagagtg tgacattgttggaataatcattgaaaatgactaacacaagaccctgtaaatacatgataattgcacacagattttacatatttg cagaccaaaaatgatttaaaacaagttgtagtcttctatggttttg 179 226777_ tataaggtaactctttagtcctccatttagcacattttaaatcctccaaagaataagtatcatgtgattattttagctttacaaaaa at aaaagttgaatggcgttttattttcatggcctataagcaggtaccttagtagggcagatataggaaaaacaaattagagcaa aacaaatcctctacaaatccaaggcaggaaaagtggtggcagagtgactcattctcctgtccctcccatcaggtcaaatc aggaggctgcagtgaatgcctgttctttgaatgtgtagcagttgttncctgtaactctttaaaacttggctataggctgtttag cacagtacagattaaagatacagttacgtaaacagcaaagtaattttatagtgcttcatccatttatcatgctttggtttgctaa ttnttcacatacctttttctatcacagtctgttgcnttgtacacatttctcatattggggttcgaca 180 226835_ ggagtgtggtacttctcctagttgcagtcaggcttcatacgctattgtcctgcccgttagagcagccagcgggtacagaat s_at ggattttggaagagggagtcaccactggacctccaaggaagccacgtgcagacatctacaaccttcgatctcctgacga gtttattgttggccaaaaccaggctttgattgaaccaggatgaatgcgggtgttggaagtag 181 227140_ ttaccctctatttaaatgctttgaaaaacagtgcattgacaatgggttgatatttttctttaaaagaaaaatataattatgaaagc at caagataatctgaagcctgattattttaaaactttttatgttctgtggttgatgttgtttgtttgtttgtttctattttgttggttntt actttgattttgttttgttttgttttgttttgcatactacatgcagttctttaaccaatgtctgtttggctaatgtaattaaagttgtt aatttatatgagtgcatttcaactatgtcaatggtttcttaatatttattgtgtagaagtactggtaattntttatttacaatatgttt aaagagataacagtttgatatgattcatgtgtttatagcagaagttatttatttctatggcattccagcggatattttggtgtttgcgag gcatgcagtcaatattngtacagttagtggacagtattcagcaacgcctgatagcnctttggcctt 182 227174_ ctggcacaaccctgacattactaagtggaaatgttaggatttttcggcatcgcatgttagaatctctaaaatttaaacattcct at gttaaatgactaaggtttgcnttatcaatatgaattctgaaggccaatatcataccattaactatgaaagcnttaattcctaaa aatagttttagagatattcaagcaatgctctcctaatatccatacgcaagtgtgtttatgacacaaattcactagtctgtttaaa aatgaattctttatattgactggtgttccacatatttcagtaatttctgttatgagaggacttgaaatagcaaattgccacacag ttaactggatagaccangtacgtggtgatcataaccacttggtactacacccagaaactcaaaattgtctttctcctgatga gatatgggtgtccttttgtacgtctaggcctaggtaaccagtggagtgattatattagcaaatgtgtttgtatccagagtcttc c 183 227475_ ccaggcttcgtcttatttctactgtttttgtcgcaacttccattgatttatgtcccttccctcccccctaagtacatcagggaacc at tttccacactataaatgatatgactactgtttggggtttctgggcccccatccgtgtacgtatgtggcatttccaggtatgact gagtgtgagagacatgtcagaggctcttcagtgatttcttgctattgaccgatgcttcactgtgccaaaagagaaaaaaaa tgttgggttngtaattaaattatttatatatttttgaaacccgaattgaaaatgttgcaggcaacgggctacagctttattagtg gttctctaactgtggtctccttgggccaagcaatttctttaaaggaaaagttgattatgtatgtggggtgccaggaccactgc cttgaaagca 184 228303_ tagcccaaccctatcattttcatattatgaaactgagtccaggtaagtgaatctgtccaaggtcacccagcaaggtatcagt at agccctgagggtaaggactctgataaggctcgggagggtcctggaaagcctgaggcggcaggaagagtgtgcagag ttgagcgtgtctggaaggctgatccactgctgggcccacatcaaagcccccatggggagcagacccgactgcacatgg ctcttttgctggaagaagagcatngctgcgcagaggactaaaatttcatctgggaaggcttcttttgactgtcagtagcag gatgtcaccagatgagggtgctatgggaccacagctgtctttgttcccattgcaactcaaccctgcnggaggccgcctgc atccctgagagccttctggagcctacagaggagacattggccagccaaaaggaaaggagtggccagggtacgacct 185 228653_ aattatcccttatcattccaaaaatgaaatgctgtgttaaatatctccagggcaaagtggtatgttgactgggacaaacgtta at gaaattgtattgttcattgcacttgttgccctgttccccaagcttgtcaatgtttagagatactattcgggttgctaaagccatta ttcatagaaaatttctgcccctacagaagtgtgtgcatgggccttggaaaatctacatgtgtatatctgagtagcgaagcac agattcactctaattgaaagcagcagtttggttngtaaatgtaattgcaattgacactttcttttccctttcagttattatttttnta aaggacgttatgagaaggcactatgaaaagcctaattggaatagcattatgaaccatgtaatgcatgcccatgcacactgt gatttgcaaacatatgtccgctcttcaat 186 228754_ ggtgggtgtcactacagacatgttctggcgtgttctccgagggatggagcatcctgttatatatttgacttcaaattgagatg at ttggcttcattttttttttttacccaattaatctcccaatccctagcaactgtgactctgtatttagcacaagagaaagctgagaa tgtgggtcttgcctccttccagaaatatgtctggctcatcaggacattatttaaaacttcaaaatattntaagatattttaaactt ttataaaaaaaaaatcaaccaacaagagacttttctgaggaggaacatttgtatttgaacaagatccttggtgtgtagttcag tcttgcagtatacaagcnttgtgtataaatgattatgatatgattccctgtnttttgcaggggttntttctcttttgcntttagata aatatgtatatcaatattttaaattcatctttgcnttntagaggagtttgtaatcaccttataac 187 228915_ gaaaaaagctatcagctgtatgttaagagagactcttactaacatgttgtaaatattacaattcatgaaatgttattgtaagtct at gtaacttaattattccctgattagttatacaggttggtttggaaatttgtgattggcataaacaagtaaaatgtgcccattttat ggtttccatgcnttgtaatcctaaaaatattaatgtctagttgttctatattataaccacatttgcgctctatgcaagcccttgga acagaacatactcatcttcatgtaggacctatgaaaattgtctattntatctatatatttaaagttnctaaaaatgataaaaggt tattacgaattngttgtacaaaatctgtacaaaaatctgatttacatcataatgcaagaattggaaatttttctatggtagccta gttatttgagcctggtttcaatgtgaga 188 229215_ gccgcggtggaaacgggcttggagctggccccataangggctngcggcttcctccgacgccgcccctccccacagct at tctcgactgcagtggggcggggggcaccaacacttggagatttttccggaggggagaggattttctaagggcacagag aatccattttctacacattaacttgagctgctggagggacactgctggcaaacggagacctatttttgtacaaagaaccctt gacctggggcgtaataaagatgacctggacccctgcccccactatctgnngnnnnnnntgctggccaagatctggac acgagcagtccctgaggggcggggtccctggcgtgaggcccccgtgacagcccaccctggggtgggtttgtgggca ctgctgctctgctagggagaagcctgtgtggggcacacctcttcaagggagcgtga 189 229802_ gacatgattgtctataatctcgctagccttgtactgtgtgtgcatagcaattacagggaagtaatctagctcctgactattatg at ttgaactatgtcgctgcntttacaaacttgtcttgatccaaagcagtcacaatgataaccctgcatatctgggaatcataagt caactatgtatctctgtgtgtgtatatatatgtatgtatgtatctattttcaaactgtgatttaatatttaaatattcctactgccattt ttgtgactgaaaaactacacatgaggaaacgtcttagaattttccaatagaggaaaaataacacttgggcaatctgtcatgt ttcacaacagttctcatttttctcatgatttgtgtagcgtggaatgtgtttgctcaatgtgaagggttttcattgctcaatttctctg tgtaa 190 231766_ ggttccggctaacacattttctaagtcgccagtgctgcttacagtttgaatacatgaaaatcctgtttctnagatgtttgcgca s_at cgtgcttattaggaaatgagtctgtatggaaatctcaccacagataatggttaacgaaccgggtcgacatcacaaaggag ggtggagactctttttactaacttgaatgagacaaaagcagtggtgtcagtttataatcctgatgcatttcagtaataatgtag aaaaacattattttaaaaaagttccaacacacagccatgaggagccnnnnnnnnnntcagttttgaaagaggtgcataa taaaactactaaccagaggagtctatgccatttt 191 231832_ gagtttcaactttaaatgttcactatgtcatttagtgtccanctttacggataggttgactatctaaataggcatttttagtcatta at aaaaaaantctagtcaccaggaggatccctataactcaaaataacttgtttgtaaaagaaaatttgtttacttacccattagta agttcctgcatattcattataagatggcaaatcaaacttnctaggatgaagacagcttattntaagttgtatagtcttagttgg tttagggtctcaattttaattaataaaatacttggttntatttgcttgtccttttgaattcctgattaataattttaaaatgagcaca aagaangttgaagttcagattaatctcttctgaatgatgatttttcctctgtgatgagttgtttctg 192 231941_ caccaagttacgtcaaagtctcaggagcagctccggtctccatagaggctgggtcagcagtgggcaaaacaacttccttt s_at gctgggagctctgcttcctcctacagcccctcggaanncncnctcaagaacttcaccccttcagagacaccgaccatgg acatcncaaccaaggggnccttccccaccagcanggaccctcttccttctgtccctccgactacaaccaacagcagcc ganngacgaacagcacntnnnnnaagatcacaacctcagcgaagaccacgatgaagcccc 193 232151_ gtacagcatgaaaggcttcctctacaagacactagtcaaagagttgagagctgcggtttctaatctttgtccattactccctt at atactccctatgagactgtggacctgtcacttggcctctctggtcttcagttttctcaccagtaaaacaaggaacttgaaccaa atgacctctagtgttccccttgggtttaaatgtctataaatgttcaatgactagaannnantgcgtttttctttattctttttgcttt gagaaaagagaatgtgatttaagagtaataatttgaataccaattatccacattaaaattgtgtcctctatgtgtaaggcata gcacatttagcacacatacataagcacactaagcaccttacaaatatcctcatttattctttacataatcttttgaaatngattat gtaatacacacngttttnnaacaatnggtgacttccagctgtttaaaacaaactacagtatggtgcttgagtactgacttag gaggtcagcatnggtttcactaggagcttctcaaagcacgctgcc 194 232176_ gggatcactgggagaagccatggcattatcttcaggcaatttagtctgtcccaaataaaataaatccttgcatgtaaatcatt at caagggttatagtaatatttcatatactgaaaagtgtctcataggagtcctcttgcacatctaaaaaggctgaacatttaagta tcccgaattttcttgaattgctttccctatagattaattacaattggatttcatcatttaaaaaccatacttgtatatgtagttataat atgtaaggaatacattgtttataaccagtatgtacttcaaaaatgtgtattgtcaaacatacctaactttcttgcaataaatgca aaagaaactggaacttgacaattataaatagtaatagtgaagaaaaaatagaaaggttgcaattatataggccatgggtg gctcaaaactttgaa 195 232252_ ggacgatgaagccatcattgctgcttggagacgccggcaagaagaaaccaggaccaagctgcagaaaaggaggga at ggactgagctggggaaaatctgagaacactgaaagaaaccactcacgttagcatagggctcagggcacacgttgcca ccactcatcgcaggatgaggatacagagaggatcttccagaggggcagagccaaaatgagagntaccaagcatnng ggcannngaggtggagtagggaggaggcaaggagggggagaaccatcaatacgaatacgaggtccgaatgcgga ccaactgataccattttctgttgctcagcgccctctaagctttggtgtttcacttaatgtatttgacagtgttcatcacaggcta gagaggtgagcttggaaaagcactgtagtttgtcagagactccagtttacatccagaaaggccatgaacataggacacg cttctgtctgtagaggcttcatatgagacccagaaagtctatcctatggcaagtctgacctctcctggcaatgctcagttctg att 196 232481_ gaagtccatcctttggtccaaagcatctggaagaggaagaagagaggaatgagaaagaaggaagtgatgcaaaacat s_at ctccaaagaagtcttttggaacaggaaaatcattcaccactcacagggtcaaatatgaaatacaaaaccacgaaccaatc aacagaatttttatccttccaagatgccagctcattgtacagaaacattttagaaaaagaaagggaacttcagcaactggg aatcacagaatacctaaggaaaaacattgctcagctccagcctgatatggaggcacattatcctggagcccacgaagag ctgaagttaatggaaacattaatgtactcacgtccaaggaaggtattagtggaacagacaaaaaatgagtattttgaactta aagctaatttacatgctgaacctgactatttagaagtcctggagcagcaaacatagatggagagtttgagggctttcgcag aaatgctgtgattctgttttaagtccataccttgtaaataagtgccttacgtgagtgtgtcatcaatcagaacctaagc 197 234331_ accaagatggtgcaagttccctttgcagatggcgtgggcacacttgatttttattatgagtgaatgtaatctttctgtattttac s_at cagagttacagcaattacctgaaaagtttcctaacattttaataatgttagggatttcgttttggttttagttgtcctcaagagac aacaggttcacagtaatttccatgatgttgggtgtggctaagctggggattggttctgttccccctgctcccgtgtagagaa aagctatatttatactgcattctttctcaactttcaggtaaaacaaactatgatttaaaaaaagaaaaaagaaaagacaggta cattacttcaaagagtgctttgctacattntatttaaaccaaaaatcaaataaaataaggaggggggctgggtatactttaa acaaaaccagtcctgaaatgctgttatt 198 235210_ ttcttgtccagctgttcacagttttatttttatatagatggtgatataaatatttccaaatgcatttgtaaacattctaaatattctca s_at agtcatgttcaatgtttcctaaaccttcaattttggccaaagtccccaaacacatcattgccacactctgaagtagagaaag aaaatttaggggccagttctcaaggaacacaggtcctttatttttattttaactaagttgaagacccactcaaaaagctcttgt ggttttatgttcttgacctttcaactggagtcctctcattcagcaggtggcccgtgagacacagaatac 199 235976_ cagtgctgctgtgaactaaagtatgtcatttatgctcaaagtttaattcttcttcttgggatattttaaaaatgctactgagattct at gctgtaaatatgactagagaatatattgggtttgctttatttcataggcttaattctttgtaaatctgaatgaccataatagaaat acatttcttgtggcaagtaattcacagttgtaaagtaaataggaaaaattattttatttttattgatgtacattgatagatgccata aatcagtagcaaaaggcacttctaaaggtaagtggtttaagttgcctcaanagagggacaatgtagctttattttacaagaa ggcatagttagatttctatgaaatatttattctgtacagttttatatanttttggttcacaaaagtaattattcttgggtgcctttca a 200 236894_ aaagtatattgtgctagcttgtctaagaataaacttnnatactgttgggggagggctgcacctgtcaagataacctgtcaat at gtagtaggaaaacaggaggggacagtaacagaaaagcacgggaaaagatggcaaggttagttaaaatagaaaagtg ctcagttcctcatacctgtaatcccagcagtttagggggccaaggaaggtgggtcacttgagcccaagagttcaaggcc atcctgggcaatgtggcgaaagtgtctacaaaaaaatacaaaaagaggaagaaatgatatttcacaagtttgtatcatttgt cat 201 238017_ caaaaccacgattgtgtgccccttttttatnaaanctggnatgtttgaangttgtantacangctntncttctntgttgccaat at tctgnnacnnnnntnnnnannngaaaaaatagtagaagctattctacaagaaaaaatgtacttgtatatgccaaagttgt tatacttcatgatgtttcttaaaagctttttgcccctcaagacaggactgcttatagctgactatttgggcatccttcatgcaat ggatggctttgttgaccaaaagaagaagctctaaagaccaactctatggctaaggtcatctgatacacagtgttacataat gcgtacttcaatgaagaaaagtatttttgtctgacagtggaatatatctggagaccacaagtaccactcctattctgttatctg g 202 238021_ agccgttggtctttgaaatttcctgtgatgtgtttcaatctagatgcaaagaacatggaaaaatcaaagtgctcgagtggttt s_at aaatatgttttgggtattcctgtttatagactataatacttttccaattaaaatcctcagttgtcacgcagaagaaggttaagct gtatttgattgccagttttactgaaaatgcttagtattttacagtatcaccaaatatattttgtttagccaaggtatagga acccaacaagagctgtgcggctccctgattcctcgccagtgttgctaccgcccttggctcttcttgcatggctggctcttga gacccctggaagctgatggaggcaacgtgagaagcacatggacatccgnccntgagcttgagaggcagaggcctga 203 238984_ gttctagttacagccccagcagtaccagttgtgtggactgggagggaggcnatcacgtacatactccaagcctccaagc at ctgtttccccttctgacacaggatcttttgtggctggtatanagtgggcactcaataaatgctgtctggtcgtctggctggca tgcctnatgggcctgagaattgaatagaattacagtgatagaagcatgctggtattgtaagtggtttgtaagtgtgaggact aaattattattaaatagtaatcacatctaatcttggataaattagtaaaagcaagaatgggagcagtaaaaacctaagcaac ccgaactaaaattttattgaattaattcaatttcttgtcatgtaacacaaccccaga 204 241031_ gtttctgtttcagtcacaaattagggttattgtgatgtgtatttatgatgaccnttgaacaaatgtgaagaatactgtgaattcta at tgactttatcaaaatcagccacatccaggagcttgcagttgttgaccaaatgaatgatgacatagagtagttcagatctatc atgtgctcttctatctaatcagtcaatatttccttggccctcaagccaacattcattnttatgtataaccttcttcatgattttgaa attttgatagggtaactgctaatgagttcacaaatgtagcactttaaaaggaaaataaatggagagtgaaaacaacttggct acgtataattgtgggt 205 37892_ caacccattttgtgccacatgcaagttttgaataaggatggtatagaaaacaacgctgcatatacaggtaccatttaggna at nnancngatgcctttntgggggcagaatcacatggcaaaagctttgaaaatcataaagatataagttggtgtggctaaga tggaaacagggctgattcttgattcccaattctcaactctccttttcctatttgaatttctttggtgctgtagaaaacaaaaaaa gaaaaatatatattcataaaaaatatggtgctcattctcatccatccaggatgtactaaaacagtgtgtttaataaattgtaatt attttgtgtacagttctatactgttatctgtgtccatttccaaaacttgcacgtgtccctgaattcc 206 60474_ acagacttggcaagggaccccctggttctgagccagtagctgccatctggaaattcctcttttnnnnnnnnnnnnnnn at nnnnnnnnnnnnnnnnnctcccaggnacccgctgaatttctgaggccttgcttaaagctcagaagtggtttaggcatt tggaaaatctggttcacatcataaagaacttgatttgaaatgattctatagaaacaagtgctaagtgtnaccgtattatacttg atgttggtcatttctcagtcctatttctcagttctattattttagaacctagtcagttctttaagattataactggtcctacattaaaa taatgcttctcgangtcagattttacctgtttgctgctgagaacatctctgcctaannnnnnnnnnnnnnnncttcagttc aacatgcttccttagcttttcatagttgtctgacatttccatgaaa

BIBLIOGRAPHY

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1. A method of screening for the onset or predisposition to the onset of a large intestine neoplasm or monitoring the progress of a neoplasm in an individual, said method comprising measuring the level of expression of one or more genes or transcripts selected from: (i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 201195_s_at; and/or (ii) SLC7A5 in a biological sample from said individual wherein a higher level of expression of the genes or transcripts of group (i) and/or group (ii) relative to control levels is indicative of a neoplastic large intestine cell or a cell predisposed to the onset of a neoplastic state.
 2. The method according to claim 1 wherein said control level is a non-neoplastic level.
 3. The method according to claim 1 wherein said neoplastic cell is an adenoma or an adenocarcinoma.
 4. The method according to claim 1 wherein said cell is a colorectal cell.
 5. The method according to claim 1 wherein said biological sample is a faecal sample, enema wash, surgical resection, tissue biopsy or blood sample.
 6. The method according to claim 1 wherein said level of expression is mRNA expression or protein expression.
 7. The method according to claim 1 wherein said biological sample is a fecal sample, enema wash, surgical resection, tissue biopsy or blood sample.
 8. The method according to claim 1 wherein said individual is a human. 